Methods and compositions for treating flaviviridae infections

ABSTRACT

A method and composition for treating a host infected with flavivirus or pestivirus comprising administering an effective flavivirus or pestivirus treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

This invention is in the area of pharmaceutical chemistry, and inparticular, is a compound, method and composition for the treatment offlaviviruses and pestiviruses. This application claims priority to U.S.provisional application No. 60/207,674, filed on May 26, 2000 and U.S.provisional application No. 60/283,276, filed on Apr. 11, 2001.

BACKGROUND OF THE INVENTION

Pestiviruses and flaviviruses belong to the Flaviviridae family ofviruses along with hepatitis C virus. The pestivirus genus includesbovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV,also called hog cholera virus) and border disease virus (BDV) of sheep(Moennig, V. et al. Adv. Vir. Res. 1992, 41, 53-98). Pestivirusinfections of domesticated livestock (cattle, pigs and sheep) causesignificant economic losses worldwide. BVDV causes mucosal disease incattle and is of significant economic importance to the livestockindustry (Meyers, G. and Thiel, H.-J., Advances in Virus Research, 1996,47, 53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41, 53-98).

Human pestiviruses have not been as extensively characterized as theanimal pestiviruses. However, serological surveys indicate considerablepestivirus exposure in humans. Pestivirus infections in man have beenimplicated in several diseases including congenital brain injury,infantile gastroenteritis and chronic diarrhea in human immunodeficiencyvirus (HIV) positive patients. M. Giangaspero et al., Arch. Viral.Suppl., 1993, 7, 53-62; M. Giangaspero et al., Int. J. Std. Aids, 1993,4 (5): 300-302.

The flavivirus genus includes more than 68 members separated into groupson the basis of serological relatedness (Calisher et al., J. Gen. Viral,1993, 70, 37-43). Clinical symptoms vary and include fever, encephalitisand hemorrhagic fever. Fields Virology, Editors: Fields, B. N., Knipe,D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia,Pa., 1996, Chapter 31, 931-959. Flaviviruses of global concern that areassociated with human disease include the dengue hemorrhagic feverviruses (DHF), yellow fever virus, shock syndrome and Japaneseencephalitis virus. Halstead, S. B., Rev. Infect. Dis., 1984, 6,251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T. P., NewEng. Med., 1988, 319, 641-643.

Examples of antiviral agents that have been identified as active againstthe flavivirus or pestiviruses include:

-   -   (1) interferon and ribavirin (Battaglia, A. M. et al., Ann.        Pharmacother, 2000, 34, 487-494); Berenguer, M. et al. Antivir.        Ther., 1998, 3 (Suppl. 3), 125-136);    -   (2) Substrate-based NS3 protease inhibitors (Attwood et al.,        Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et        al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273;        Attwood et al., Preparation and use of amino acid derivatives as        anti-viral agents, German Patent Pub. DE 19914474; Tung et al.        Inhibitors of serine proteases, particularly hepatitis C virus        NS3 protease, PCT WO 98/17679), including alphaketoamides and        hydrazinoureas, and inhibitors that terminate in an electrophile        such as a boronic acid or phosphonate (Llinas-Brunet et al,        Hepatitis C inhibitor peptide analogues, PCT WO 99/07734).    -   (3) Non-substrate-based inhibitors such as        2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al.,        Biochemical and Biophysical Research Communications, 1997, 238,        643-647; Sudo K. et al. Antiviral Chemistry and Chemotherapy,        1998, 9, 186), including RD3-4082 and RD3-4078, the former        substituted on the amide with a 14 carbon chain and the latter        processing a para-phenoxyphenyl group;    -   (4) Thiazolidine derivatives which show relevant inhibition in a        reverse-phase HPLC assay with an NS3/4A fusion protein and        NS5AJ5B substrate (Sudo K. et al., Antiviral Research, 1996, 32,        9-18), especially compound RD-1-6250, possessing a fused        cinnamoyl moiety substituted with a long allyl chain, RD4 6205        and RD4 6193;    -   (5) Thiazolidines and benzanilides identified in Kakiuchi N. et        al. J. EBS Letters 421, 217-220; Takeshita N. et al. Analytical        Biochemistry, 1997, 247, 242-246;    -   (6) A phenan-threnequinone possessing activity against protease        in a SDS-PAGE and autoradiography assay isolated from the        fermentation culture broth of Streptomyces sp., Sch 68631        (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), and        Sch 351633, isolated from the fungus Penicillium griscofuluum,        which demonstrates activity in a scintillation proximity assay        (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9,        1949-1952);    -   (7) Selective NS3 inhibitors based on the macromolecule elgin c,        isolated from leech (Qasim M. A. et al., Biochemistry, 1997, 36,        1598-1607);    -   (8) Helicase inhibitors (Diana G. D. et al., Compounds,        compositions and methods for treatment of hepatitis C, U.S. Pat.        No. 5,633,358; Diana G. D. et al., Piperidine derivatives,        pharmaceutical compositions thereof and their use in the        treatment of hepatitis C, PCT WO 97/36554);    -   (9) Polymerase inhibitors such as nucleotide analogues,        gliotoxin (Ferrari R. et al. Journal of Virology, 1999, 73,        1649-1654), and the natural product cerulenin (Lohman V. et al.,        Virology, 1998, 249, 108-118);    -   (10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN)        complementary to sequence stretches in the 5′ non-coding region        (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22,        707-717), or nucleotides 326-348 comprising the 3′ end of the        NCR and nucleotides 371-388 located in the core coding region of        the IICV RNA (Alt M. et al., Archives of Virology, 1997, 142,        589-599; Galderisi U. et al., Journal of Cellular Physiology,        1999, 181, 251-257);    -   (11) Inhibitors of IRES-dependent translation (Ikeda N et al.,        Agent for the prevention and treatment of hepatitis C, Japanese        Patent Pub. JP-08268890; Kai Y. et al. Prevention and treatment        of viral diseases, Japanese Patent Pub. JP-10101591);    -   (12) Nuclease-resistant ribozymes (Maccjak, D. J. et al.,        Hepatology 1999, 30, abstract 995); and    -   (13) Other miscellaneous compounds including        1-amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134 to Gold et        al.), alkyl lipids (U.S. Pat. No. 5,922,757 to Chojkier et al.),        vitamin E and other antioxidants (U.S. Pat. No. 5,922,757 to        Chojkier et al.), squalene, amantadine, bile acids (U.S. Pat.        No. 5,846,964 to Ozeki et al.), N-(phosphonoacetyl)-L-aspartic        acid, (U.S. Pat. No. 5,830,905 to Diana et benzenedicarboxamides        (U.S. Pat. No. 5,633,388 to Diana at al.), polyadenylic acid        derivatives (U.S. Pat. No. 5,496,546 to Wang et al.),        2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687 to Yarchoan et        al.), and benzimidazoles (U.S. Pat. No. 5,891,874 to Colacino et        al.).

In view of the severity of diseases associated with pestiviruses andflaviviruses, and their pervasiveness in animal and man, it is an objectof the present invention to provide a compound, method and compositionfor the treatment of a host infected with flavivirus or pestivirus.

SUMMARY OF THE INVENTION

Compounds, methods and compositions for the treatment of a host infectedwith a flavivirus or pestivirus infection are described that includes aneffective treatment amount of a or β-L-nucleoside of the Formulas(I)-(XVIII), or a pharmaceutically acceptable salt or prodrug thereof.

In a first principal embodiment, a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H, phosphate (including mono-, di- ortriphosphate and a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹, R²or R³ is independently H or phosphate;Y is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ and X² are independently selected from the group consisting of H,straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl,CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a second principal embodiment, a compound of Formula II, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate; andY is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ and X² are independently selected from the group consisting of H,straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl,CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a third principal embodiment, a compound of Formula III, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate; andY is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ and X² are independently selected from the group consisting of H,straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl,CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a fourth principal embodiment, a compound of Formula IV, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H, phosphate (including mono-, di- ortriphosphate and a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹, R²or R³ is independently H or phosphate;Y is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ is selected from the group consisting of H, straight chained,branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro,bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a fifth principal embodiment, a compound of Formula V, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate; andY is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ is selected from the group consisting of H, straight chained,branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro,bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a sixth principal embodiment, a compound of Formula VI, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate; andY is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ is selected from the group consisting of H, straight chained,branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro,bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a seventh principal embodiment, a compound selected from FormulasVII, VIII and IX, or a pharmaceutically acceptable salt or prodrugthereof, is provided:

wherein:Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(loweralkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl),—O(alkenyl), CF₃, chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂; and

X is O, S, SO₂ or CH₂.

In a eighth principal embodiment, a compound of Formulas X, XI and XII,or a pharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂;R⁷ is hydrogen, OR³, hydroxy, alkyl (including lower alkyl), azido,cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chlorine, bromine, iodine, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂; and

X is O, S, SO₂ or CH₂.

In a ninth principal embodiment a compound selected from Formulas XIII,XIV and XV, or a pharmaceutically acceptable salt or prodrug thereof, isprovided:

wherein:Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂; and

X is O, S, SO₂, or CH₂.

In a tenth principal embodiment the invention provides a compound ofFormula XVI, or a pharmaceutically acceptable salt or prodrug thereof:

wherein:Base is a purine or pyrimidine base as defined herein;R¹ and R² are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹ or R² is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower allyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂;R⁷ and R⁹ are independently hydrogen, OR², hydroxy, alkyl (includinglower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl),—C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(loweralkyl), —O(alkenyl), chlorine, bromine, iodine, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂;R⁸ and R¹⁰ are independently H, alkyl (including lower alkyl), chlorine,bromine or iodine;alternatively, R⁷ and R⁹, R⁷ and R¹⁰, R⁸ and R⁹, or R⁸ and R¹⁰ can cometogether to form a pi bond; and

X is O, S, SO₂ or CH₂.

In a eleventh principal embodiment the invention provides a compound ofFormula XVII, or a pharmaceutically acceptable salt or prodrug thereof:

wherein:Base is a purine or pyrimidine base as defined herein;R¹ and R² are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹ or R² is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂;R⁷ and R⁹ are independently hydrogen, OR², hydroxy, alkyl (includinglower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl),—C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(loweralkyl), —O(alkenyl), chlorine, bromine, iodine, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂;R¹⁰ is H, alkyl (including lower alkyl), chlorine, bromine or iodine;alternatively, R⁷ and R⁹, or R⁷ and R¹⁰ can come together to form a pibond; and

X is O, S, SO₂ or CH₂.

In an twelfth principal embodiment, the invention provides a compound ofFormula XVIII, or a pharmaceutically acceptable salt or prodrug thereof:

wherein:Base is a purine or pyrimidine base as defined herein;R¹ and R² independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹ or R² is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂;R⁷ and R⁹ are independently hydrogen, OR², alkyl (including loweralkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino or di(lower-alkyl)amino;R⁸ is H, alkyl (including lower alkyl), chlorine, bromine or iodine;alternatively, R⁷ and R⁹, or R⁸ and R⁹ can come together to form a pibond;

X is O, S, SO₂ or CH₂.

The β-D- and β-L-nucleosides of this invention may inhibit flavivirus orpestivirus polymerase activity. These nucleosides can be assessed fortheir ability to inhibit flavivirus or pestivirus polymerase activity invitro according to standard screening methods.

In one embodiment the efficacy of the anti-flavivirus or pestiviruscompound is measured according to the concentration of compoundnecessary to reduce the plaque number of the virus in vitro, accordingto methods set forth more particularly herein, by 50% (i.e. thecompound's EC₅₀). In preferred embodiments the compound exhibits an EC₅₀of less than 15 or preferably, less than 10 micromolar in vitro.

In another embodiment, the active compound can be administered incombination or alternation with another anti-flavivirus or pestivirusagent. In combination therapy, effective dosages of two or more agentsare administered together, whereas during alternation therapy aneffective dosage of each agent is administered serially. The dosageswill depend on absorption, inactivation and excretion rates of the drugas well as other factors known to those of skill in the art. It is to benoted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens and schedules should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the compositions.

HCV is a member of the Flaviviridae family; however, now, HCV has beenplaced in a new monotypic genus, hepacivirus. Therefore, in oneembodiment, the flavivirus or pestivirus is not HCV.

Nonlimiting examples of antiviral agents that can be used in combinationwith the compounds disclosed herein include:

(1) an interferon and/or ribavirin (Battaglia, A. M. et al., Ann.Pharmacother. 34:487-494, 2000); Berenguer, M. et al. Antivir. Ther.3(Suppl. 3):125-136, 1998);

(2) Substrate-based NS3 protease inhibitors (Attwood et al., Antiviralpeptide derivatives, PCT WO 98/22496, 1998; Attwood et al., AntiviralChemistry and Chemotherapy 10.259-273, 1999; Attwood et al., Preparationand use of amino acid derivatives as anti-viral agents, German PatentPublication DE 19914474; Tung et al. Inhibitors of serine proteases,particularly hepatitis C virus NS3 protease, PCT WO 98/17679), includingalphaketoamides and hydrazinoureas, and inhibitors that terminate in anelectrophile such as a boronic acid or phosphonate. Llinas-Brunet et al,Hepatitis C inhibitor peptide analogues, PCT WO 99/07734.

(3) Non-substrate-based inhibitors such as2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al.,Biochemical and Biophysical Research Communications, 238:643-647, 1997;Sudo K. et al. Antiviral Chemistry and Chemotherapy 9:186, 1998),including RD3-4082 and RD3-4078, the former substituted on the amidewith a 14 carbon chain and the latter processing a para-phenoxyphenylgroup;

(4) Thiazolidine derivatives which show relevant inhibition in areverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5Bsubstrate (Sudo K. et al., Antiviral Research 32:9-18, 1996), especiallycompound RD-1-6250, possessing a fused cinnamoyl moiety substituted witha long alkyl chain, RD4 6205 and RD4 6193;

(5) Thiazolidines and benzanilides identified in Kakiuchi N. et al. J.EBS Letters 421:217-220; Takeshita N. et al. Analytical Biochemistry247:242-246, 1997;

(6) A phenan-threnequinone possessing activity against protease in aSDS-PAGE and autoradiography assay isolated from the fermentationculture broth of Streptomyces sp., Sch 68631 (Chu M. et al., TetrahedronLetters 37:7229-7232, 1996), and Sch 351633, isolated from the fungusPenicillium griscofuluum, which demonstrates activity in a scintillationproximity assay (Chu M. et al., Bioorganic and Medicinal ChemistryLetters 9:1949-1952);

(7) Selective NS3 inhibitors based on the macromolecule elgin c,isolated from leech (Qasim M. A. et al., Biochemistry 36:1598-1607,1997);

(8) Helicase inhibitors (Diana G. D. et al., Compounds, compositions andmethods for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G.D. et al., Piperidine derivatives, pharmaceutical compositions thereofand their use in the treatment of hepatitis C, PCT WO 97/36554);

(9) Polymerase inhibitors such as nucleotide analogues, gliotoxin(Ferrari R. et al. Journal of Virology 73:1649-1654, 1999), and thenatural product cerulenin (Lohmann V. et al., Virology 249:108-118,1998);

(10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN)complementary to sequence stretches in the 5′ non-coding region (NCR) ofthe virus (Alt M. et al., Hepatology 22:707-717, 1995), or nucleotides326-348 comprising the 3′ end of the NCR and nucleotides 371-388 locatedin the core coding region of the IICV RNA (Alt M. et al., Archives ofVirology 142:589-599, 1997; Galderisi U. et al., Journal of CellularPhysiology 181:251-257, 1999);

(11) Inhibitors of IRES-dependent translation (Ikeda N et al., Agent forthe prevention and treatment of hepatitis C, Japanese Patent PublicationJP-08268890; Kai Y. et al. Prevention and treatment of viral diseases,Japanese Patent Publication JP-10101591);

(12) Nuclease-resistant ribozymes. (Maccjak D. J. et al., Hepatology 30abstract 995, 1999); and

(13) Other miscellaneous compounds including 1-amino-alkylcyclohexanes(U.S. Pat. No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Pat. No.5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S.Pat. No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids(U.S. Pat. No. 5,846,964 to Ozeki et al.),N-(phosphonoacetyl)-L-aspartic acid, (U.S. Pat. No. 5,830,905 to Dianaet al.), benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana etal.), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang etal.), 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687 to Yarchoan et al.),and benzimidazoles (U.S. Pat. No. 5,891,874 to Colacino et

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides the structure of various non-limiting examples ofnucleosides of the present invention, as well as other knownnucleosides, FIAU and Ribavirin, which are used as comparative examplesin the text.

FIG. 2 is a line graph of the pharmacokinetics (plasma concentrations)of β-D-2′-CH₃-riboG administered to Cynomolgus Monkeys over time afteradministration.

FIGS. 3 a and 3 b are line graphs of the pharmacokinetics (plasmaconcentrations) of β-D-2′-CH₃-riboG administered to Cynomolgus Monkeyseither intravenously (3 a) or orally (3 b) over time afteradministration.

FIG. 4 depicts line graphs of the results of the cell protection assayof β-D-2′-CH₃-riboG against BVDV.

FIG. 5 depicts line graphs of the results of the cell protection assayof ribavirin against BVDV.

FIG. 6 are line graphs of the cell protection assay of β-D-2′-CH₃-riboG,β-D-2′-CH₃-riboC, β-D-2′-CH₃-riboA and ribavirin.

FIG. 7 are line graphs of the results of the plaque reduction assay forβ-D-2′-CH₃-riboU, β-D-2′-CH₃-riboC and β-D-2′-CH₃-riboG.

FIG. 8 is illustration of plaque reduction based on increasingconcentrations of β-D-2′-CH₃-riboU.

FIG. 9 is a line graph of the results of the yield reduction assay forβ-D-2′-CH₃-riboG, depicting a 4 log reduction at 9 μM.

FIG. 10 is an illustration of the yield reduction based on increasingconcentrations of β-D-2′-CH₃-riboC.

DETAILED DESCRIPTION OF THE INVENTION

The invention as disclosed herein is a compound, method and compositionfor the treatment of pestiviruses and flaviviruses in humans and otherhost animals, that includes the administration of an effectiveflavivirus or pestivirus treatment amount of an β-D- or β-L-nucleosideas described herein or a pharmaceutically acceptable salt or prodrugthereof, optionally in a pharmaceutically acceptable carrier. Thecompounds of this invention either possess antiviral (i.e.,anti-flavivirus or pestivirus) activity, or are metabolized to acompound that exhibits such activity.

In summary, the present invention includes the following features:

-   -   (a) β-D- and β-L-nucleosides, as described herein, and        pharmaceutically acceptable salts and prodrugs thereof;    -   (b) β-D- and β-L-nucleosides as described herein, and        pharmaceutically acceptable salts and prodrugs thereof for use        in the treatment or prophylaxis of a flavivirus or pestivirus        infection, especially in individuals diagnosed as having a        flavivirus or pestivirus infection or being at risk for becoming        infected by flavivirus or pestivirus;    -   (c) use of these β-D- and β-L-nucleosides, and pharmaceutically        acceptable salts and prodrugs thereof in the manufacture of a        medicament for treatment of a flavivirus or pestivirus        infection;    -   (d) pharmaceutical formulations comprising the β-D- and        β-L-nucleosides or pharmaceutically acceptable salts or prodrugs        thereof together with a pharmaceutically acceptable carrier or        diluent;    -   (e) β-D- and β-L-nucleosides as described herein substantially        in the absence of enantiomers of the described nucleoside, or        substantially isolated from other chemical entities;    -   (f) processes for the preparation of β-D- and β-L-nucleosides,        as described in more detail below; and    -   (g) processes for the preparation of β-D- and β-L-nucleosides        substantially in the absence of enantiomers of the described        nucleoside, or substantially isolated from other chemical        entities.

Flaviviruses included within the scope of this invention are discussedgenerally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., andHowley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., Chapter31, 1996. Specific flaviviruses include, without limitation: Absettarov,Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, CareyIsland, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill,Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkeymeningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam,Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forestdisease, Langat, Louping ill, Meaban, Modoc, Montana myotisleukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya,Omsk hemorrhagic fever, Phnom-Perth bat, Powassan, Rio Bravo, Rocio,Royal Farm, Russian spring-summer encephalitis, Saboya, St. Louisencephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk,Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsbron,West Nile, Yaounde, Yellow fever, and Zika.

Pestiviruses included within the scope of this invention are discussedgenerally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., andHowley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., Chapter33, 1996. Specific pestiviruses include, without limitation: bovineviral diarrhea virus (“BVDV”), classical swine fever virus (“CSFV,” alsocalled hog cholera virus), and border disease virus (“BDV”).

I. Active Compound, and Physiologically Acceptable Salts and ProdrugsThereof

In a first principal embodiment, a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H, phosphate (including mono-, di- ortriphosphate and a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹, R²or R³ is independently H or phosphate;Y is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ and X² are independently selected from the group consisting of H,straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl,CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a preferred subembodiment, a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof, is providedwherein:

R¹, R² and R³ are independently H or phosphate (preferably H);

X¹ is H; X² is H or NH₂; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH₂ or OH.

In a second principal embodiment, a compound of Formula II, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate; andY is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ and X² are independently selected from the group consisting of H,straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl,CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a preferred subembodiment, a compound of Formula II, or apharmaceutically acceptable salt or prodrug thereof, is providedwherein:

R¹, R² and R³ are independently H or phosphate (preferably H);

X¹ is H; X² is H or NH₂; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH₂ or OH.

In a third principal embodiment, a compound of Formula III, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate; andY is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ and X² are independently selected from the group consisting of H,straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl,CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a preferred subembodiment, a compound of Formula III, or apharmaceutically acceptable salt or prodrug thereof, is providedwherein:

R¹, R² and R³ are independently H or phosphate (preferably H);

X¹ is H; X² is H or NH₂; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH₂ or OH.

In a fourth principal embodiment, a compound of Formula IV, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H, phosphate (including mono-, di- ortriphosphate and a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹, R²or R³ is independently H or phosphate;Y is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ is selected from the group consisting of H, straight chained,branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro,bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a preferred subembodiment, a compound of Formula IV, or apharmaceutically acceptable salt or prodrug thereof, is providedwherein:

R¹, R² and R³ are independently H or phosphate (preferably H);

X¹ is H or CH₃; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH₂ or OH.

In a fifth principal embodiment, a compound of Formula V, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate; andY is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ is selected from the group consisting of H, straight chained,branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro,bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a preferred subembodiment, a compound of Formula V, or apharmaceutically acceptable salt or prodrug thereof, is providedwherein:

R¹, R² and R³ are independently H or phosphate (preferably H);

X¹ is H or CH₃; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH₂ or OH.

In a sixth principal embodiment, a compound of Formula VI, or apharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate; andY is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵ or SR⁴;X¹ is selected from the group consisting of H, straight chained,branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro,bromo, fluoro, iodo, OR⁴, NR⁴NR⁵ or SR⁵; andR⁴ and R⁵ are independently hydrogen, acyl (including lower acyl), oralkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl).

In a preferred subembodiment, a compound of Formula VI, or apharmaceutically acceptable salt or prodrug thereof, is providedwherein:

R¹, R² and R³ are independently H or phosphate (preferably H);

X¹ is H or CH₃; and

Y is hydrogen, bromo, chloro, fluoro, iodo, NH₂ or OH.

In a seventh principal embodiment, a compound selected from FormulasVII, VIII and IX, or a pharmaceutically acceptable salt or prodrugthereof, is provided:

wherein:Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, 2-Br-ethyl, —C(O)O(alkyl), —C(O)O(loweralkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl),—O(alkenyl), CF₃, chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂; and

X is O, S, SO₂, or CH₂.

In a first preferred subembodiment, a compound of Formula VII, VIII orIX, or a pharmaceutically acceptable salt or prodrug thereof, isprovided wherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently hydrogen or phosphate;R⁶ is alkyl; and

X is O, S, SO₂ or CH₂.

In a second preferred subembodiment, a compound of Formula VII, VIII orIX, or a pharmaceutically acceptable salt or prodrug thereof, isprovided wherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are hydrogens;R⁶ is alkyl; and

X is O, S, SO₂ or CH₂.

In a third preferred subembodiment, a compound of Formula VII, VIII orLX, or a pharmaceutically acceptable salt or prodrug thereof, isprovided wherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently hydrogen or phosphate;R⁶ is alkyl; and

X is O.

In a eighth principal embodiment, a compound of Formula X, XI or XII, ora pharmaceutically acceptable salt or prodrug thereof, is provided:

wherein:Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂;R⁷ is hydrogen, OR³, hydroxy, alkyl (including lower alkyl), azido,cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chlorine, bromine, iodine, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(loweralkyl)₂, —N(acyl)₂; and

X is O, S, SO₂ or CH₂.

In a first preferred subembodiment, a compound of Formula X, XI or XII,or a pharmaceutically acceptable salt or prodrug thereof, is providedwherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently hydrogen or phosphate;R⁶ is alkyl; and

X is O, S, SO₂ or CH₂.

In a second preferred subembodiment, a compound of Formula X, XI or XII,or a pharmaceutically acceptable salt or prodrug thereof, is providedwherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are hydrogens;R⁶ is alkyl; and

X is O, S, SO₂ or CH₂.

In a third preferred subembodiment, a compound of Formula X, XI or XII,or a pharmaceutically acceptable salt or prodrug thereof, is providedwherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently H or phosphate;R⁶ is alkyl; and

X is O.

In even more preferred subembodiments, a compound of Formula XI, or itspharmaceutically acceptable salt or prodrug, is provided:

wherein:Base is a purine or pyrimidine base as defined herein; optionallysubstituted with an amine or cyclopropyl (e.g., 2-amino, 2,6-diamino orcyclopropyl guanosine); andR¹ and R² are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹ or R² is independently H or phosphate.

In a ninth principal embodiment a compound selected from Formula XIII,XIV or XV, or a pharmaceutically acceptable salt or prodrug thereof, isprovided:

wherein:Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in viva is capable of providing a compoundwherein R¹, R² or R³ is independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂; and

X is O, S, SO₂ or CH₂.

In a first preferred subembodiment, a compound of Formula XIII, XIV orXV, or a pharmaceutically acceptable salt or prodrug thereof, isprovided wherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently hydrogen or phosphate;R⁶ is alkyl; and

X is O, S, SO₂ or CH₂.

In a second preferred subembodiment, a compound of Formula XIII, XIV orXV, or a pharmaceutically acceptable salt or prodrug thereof, isprovided wherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are hydrogens;R⁶ is alkyl; and

X is O, S, SO₂ or CH₂.

In a third preferred subembodiment, a compound of Formula XIII, XIV orXV, or a pharmaceutically acceptable salt or prodrug thereof, isprovided wherein:

Base is a purine or pyrimidine base as defined herein;R¹, R² and R³ are independently hydrogen or phosphate;R⁶ is alkyl; and

X is O.

In a tenth principal embodiment the invention provides a compound ofFormula or a pharmaceutically acceptable salt or prodrug thereof:

wherein:Base is a purine or pyrimidine base as defined herein;R¹ and R² are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹ and R² are independently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂;R⁷ and R⁹ are independently hydrogen, OR², hydroxy, alkyl (includinglower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl),—C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(loweralkyl), —O(alkenyl), chlorine, bromine, iodine, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂;R⁸ and R¹⁰ are independently H, alkyl (including lower alkyl), chlorine,bromine or iodine;alternatively, R⁷ and R⁹, R⁷ and R¹⁰, R⁸ and R⁹, or R⁸ and R¹⁰ can cometogether to form a pi bond; and

X is O, S, SO₂ or CH₂.

In a first preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR², alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl,chlorine, bromine, iodine, NO₂, amino, loweralkylamino ordi(loweralkyl)amino; (5) R⁸ and R¹⁰ are independently H, alkyl(including lower alkyl), chlorine, bromine, or iodine; and (6) X is O,S, SO₂ or CH₂.

In a second preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl, alkenyl, alkynyl,Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂,amino, loweralkylamino, or di(loweralkyl)amino; (4) R⁷ and R⁹ areindependently OR²; (5) R⁸ and R¹⁰ are independently H, alkyl (includinglower alkyl), chlorine, bromine, or iodine; and (6) X is O, S, SO₂ orCH₂.

In a third preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl, alkenyl, alkynyl,Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂,amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷ and R⁹ areindependently OR², alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl,chlorine, bromine, iodine, NO₂, amino, loweralkylamino ordi(loweralkyl)amino; (5) R⁸ and R¹⁰ are H; and (6) X is O, S, SO₂ orCH₂.

In a fourth preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl, alkenyl, alkynyl,Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂,amino, loweralkylamino, or di(loweralkyl)amino; (4) R⁷ and R⁹ areindependently OR², alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl,chlorine, bromine, iodine, NO₂, amino, loweralkylamino, ordi(loweralkyl)amino; (5) R⁸ and R¹⁰ are independently H, alkyl(including lower alkyl), chlorine, bromine, or iodine; and (6) X is O.

In a fifth preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR¹; (5) R⁸ and R¹⁰ are independently H, alkyl (includinglower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO₂ orCH₂.

In a sixth preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR², alkyl (including lower alkyl), alkenyl, alkynyl,Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, amino,loweralkylamino, or di(loweralkyl)amino; (5) R^(a) and R¹⁰ are H; and(6) X is O, S, SO₂, or CH₂.

In a seventh preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR², alkyl (including lower alkyl), alkenyl, alkynyl,Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, amino,loweralkylamino or di(loweralkyl)amino; (5) R⁸ and R¹⁰ are independentlyH, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) Xis O.

In a eighth preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷and R⁹ are independently OR²; (5) R⁸ and R¹⁰ are hydrogen; and (6) X isO, S, SO₂ or CH₂.

In a ninth preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷and R⁹ are independently OR²; (5) R⁸ and R¹⁰ are independently H, alkyl(including lower alkyl), chlorine, bromine or iodine; and (6) X is O.

In a tenth preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷and R⁹ are independently OR², alkyl (including lower alkyl), alkenyl,alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, amino,loweralkylamino, or di(loweralkyl)amino; (5) R⁸ and R¹⁰ are hydrogen;and (6) X is O.

In an eleventh preferred subembodiment, a compound of Formula XVI, orits pharmaceutically acceptable salt or prodrug, is provided in which:(1) Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷and R⁹ are independently OR²; (5) R⁸ and R¹⁰ are hydrogen; and (6) X isO, S, SO₂ or CH₂.

In a twelfth preferred subembodiment, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR²; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O, S, SO₂,or CH₂.

In a thirteenth preferred subembodiment, a compound of Formula XVI, orits pharmaceutically acceptable salt or prodrug, is provided in which:(1) Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR²; (5) R⁸ and R¹⁰ are independently H, alkyl (includinglower alkyl), chlorine, bromine, or iodine; and (6) X is O.

In a fourteenth preferred subembodiment, a compound of Formula XVI, orits pharmaceutically acceptable salt or prodrug, is provided in which:(1) Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR², alkyl (including lower alkyl), alkenyl, alkynyl,Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, amino,loweralkylamino or di(loweralkyl)amino; (5) R⁸ and R¹⁰ are hydrogen; and(6) X is O.

In even more preferred subembodiments, a compound of Formula XVI, or itspharmaceutically acceptable salt or prodrug, is provided in which:

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is guanine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is cytosine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ andR⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is thymine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is uracil; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is phosphate; (3) R⁶ is methyl; (4) R⁷ andR⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is ethyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is propyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is butyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ ishydrogen and R⁹ is hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X isO;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is S;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is SO₂;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is CH₂;

In a eleventh principal embodiment the invention provides a compound ofFormula XVII, or a pharmaceutically acceptable salt or prodrug thereof:

wherein:Base is a purine or pyrimidine base as defined herein;R¹ is H; phosphate (including monophosphate, diphosphate, triphosphate,or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl(including lower alkyl); sulfonate ester including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl groupis optionally substituted with one or more substituents as described inthe definition of aryl given herein; a lipid, including a phospholipid;an amino acid; a carbohydrate; a peptide; a cholesterol; or otherpharmaceutically acceptable leaving group which when administered invivo is capable of providing a compound wherein R¹ is independently H orphosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂;R⁷ and R⁹ are independently hydrogen, OR², hydroxy, alkyl (includinglower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl),—C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(loweralkyl), —O(alkenyl), chlorine, bromine, iodine, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂;R¹⁰ is H, alkyl (including lower alkyl), chlorine, bromine, or iodine;alternatively, R⁷ and R⁹, or R⁷ and R¹⁰ can come together to form a pibond; and

X is O, S, SO₂ or CH₂.

In a first preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently hydrogen, OR², alkyl (including loweralkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino or di(loweralkyl)-amino; (5) R¹⁰ isH; and (6) X is O, S, SO₂, or CH₂.

In a second preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷and R⁹ are independently OR²; (5) R¹⁰ is H, alkyl (including loweralkyl), chlorine, bromine, or iodine; and (6) X is O, S, SO₂ or CH₂.

In a third preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently hydrogen, OR², alkyl (including loweralkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino or di(loweralkyl)-amino; (5) R¹⁰ isH, alkyl (including lower alkyl), chlorine, bromine or iodine; and (6) Xis O.

In a fourth preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷and R⁹ are independently OR²; (5) R¹⁰ is H; and (6) X is O, S, SO₂ orCH₂.

In a fifth preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷and R⁹ are independently OR²; (5) R¹⁰ is H, alkyl (including loweralkyl), chlorine, bromine or iodine; and (6) X is O.

In a sixth preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently hydrogen, OR², alkyl (including loweralkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (5) R¹⁰ isH; and (6) X is O.

In a seventh preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently OR²; (5) R¹⁰ is H; and (6) X is O.

In an eighth preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently hydrogen, OR², alkyl (including lower alkyl), alkenyl,alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, amino,loweralkylamino or di(loweralkyl)-amino; (5) R¹⁰ is H, alkyl (includinglower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO₂, orCH₂.

In a ninth preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently OR²; (5) R¹⁰ is H; and (6) X is O, S, SO₂,or CH₂.

In a tenth preferred subembodiment, a compound of Formula XVII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR²; (5) R¹⁰ is H; and (6) X is O, S, SO₂, or CH₂.

In even more preferred subembodiments, a compound of Formula XVII, orits pharmaceutically acceptable salt or prodrug, is provided in which:

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is guanine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is cytosine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ andR⁹ are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is thymine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is uracil; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is phosphate; (3) R⁶ is methyl; (4) R⁷ andR⁹ are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is ethyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is propyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is butyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is S;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is SO₂; or

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R¹⁰ is hydrogen; and (6) X is CH₂.

In an twelfth principal embodiment the invention provides a compound ofFormula XVIII, or a pharmaceutically acceptable salt or prodrug thereof:

wherein:Base is a purine or pyrimidine base as defined herein;R¹ is independently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate;R⁶ is hydrogen, hydroxy, alkyl (including lower alkyl), azido, cyano,alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl),—O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl),chloro, bromo, fluoro, iodo, NO₂, NH₂, —NH(lower alkyl), —NH(acyl),—N(lower alkyl)₂, —N(acyl)₂;R⁷ and R⁹ are independently hydrogen, OR², alkyl (including loweralkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, lower alkylamino, or di(loweralkyl)amino;R⁸ is H, alkyl (including lower alkyl), chlorine, bromine or iodine;alternatively, R⁷ and R⁹, or R⁸ and R⁹ can come together to form a pibond;

X is O, S, SO₂ or CH₂.

In a first preferred subembodiment, a compound of Formula XVIII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently hydrogen, OR², alkyl (including lower alkyl), alkenyl,alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, amino,loweralkylamino or di(loweralkyl)amino; (5) R⁸ is H, alkyl (includinglower alkyl), chlorine, bromine or iodine; and (6) X is O, S, SO₂ orCH₂.

In a second preferred subembodiment, a compound of Formula XVIII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di-(loweralkyl)amino; (4)R⁷ and R⁹ are independently OR²; (5) R⁸ is H, alkyl (including loweralkyl), chlorine, bromine, or iodine; and (6) X is O, S, SO₂ or CH₂.

In a third preferred subembodiment, a compound of Formula XVIII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-allyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(lower-alkyl)amino; (4)R⁷ and R⁹ are independently hydrogen, OR², alkyl (including loweralkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (5) R⁸ isH; and (6) X is O, S, SO₂ or CH₂.

In a fourth preferred subembodiment, a compound of Formula XVIII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently hydrogen, OR², alkyl (including loweralkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (5) R⁸ isH, alkyl (including lower alkyl), chlorine, bromine, or iodine; and (6)X is O.

In a fifth preferred subembodiment, a compound of Formula XVIII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently OR²; (5) R⁸ is H; and (6) X is O, S, SO₂, orCH₂.

In a sixth preferred subembodiment, a compound of Formula XVIII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently OR²; (5) R⁸ is H, alkyl (including loweralkyl), chlorine, bromine, or iodine; and (6) X is O.

In a seventh preferred subembodiment, a compound of Formula XVIII, orits pharmaceutically acceptable salt or prodrug, is provided in which:(1) Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H; phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol;or other pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4)R⁷ and R⁹ are independently hydrogen, OR², alkyl (including loweralkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (5) R⁸ isH; and (6) X is O.

In an eighth preferred subembodiment, a compound of Formula XVIII, orits pharmaceutically acceptable salt or prodrug, is provided in which:(1) Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁷and R⁹ are independently OR²; (5) R⁸ is H; and (6) X is O, S, SO₂ orCH₂.

In a ninth preferred subembodiment, a compound of Formula XVIII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR²; (5) R⁸ is H; and (6) X is O, S, SO₂, or CH₂.

In a tenth preferred subembodiment, a compound of Formula XVIII, or itspharmaceutically acceptable salt or prodrug, is provided in which: (1)Base is a purine or pyrimidine base as defined herein; (2) R¹ isindependently H or phosphate; (3) R⁶ is alkyl; (4) R⁷ and R⁹ areindependently OR²; (5) R⁸ is H; and (6) X is O.

In even more preferred subembodiments, a compound of Formula XVIII, orits pharmaceutically acceptable salt or prodrug, is provided in which:

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is guanine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is cytosine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ andR⁹ are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is thymine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is uracil; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is phosphate; (3) R⁶ is methyl; (4) R⁷ andR⁹ are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is ethyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is propyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is butyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is O;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is S;

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is SO₂; or

(1) Base is adenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷ and R⁹are hydroxyl; (5) R⁸ is hydrogen; and (6) X is CH₂.

The β-D- and β-L-nucleosides of this invention belong to a class, ofanti-flavivirus or pestivirus agents that may inhibit flavivirus orpestivirus polymerase activity. Nucleosides can be screened for theirability to inhibit flavivirus or pestivirus polymerase activity in vitroaccording to screening methods set forth more particularly herein. Onecan readily determine the spectrum of activity by evaluating thecompound in the assays described herein or with another confirmatoryassay.

In one embodiment the efficacy of the anti-flavivirus or pestiviruscompound is measured according to the concentration of compoundnecessary to reduce the plaque number of the virus in vitro, accordingto methods set forth more particularly herein, by 50% (i.e. thecompound's EC₅₀). In preferred embodiments the compound exhibits an EC₅₀of less than 15 or 10 micromolar.

HCV is a member of the Flaviviridae family; however, now, HCV has beenplaced in a new monotypic genus, hepacivirus. Therefore, in oneembodiment, the flavivirus or pestivirus is not HCV.

The active compound can be administered as any salt or prodrug that uponadministration to the recipient is capable of providing directly orindirectly the parent compound, or that exhibits activity itself.Nonlimiting examples are the pharmaceutically acceptable salts(alternatively referred to as “physiologically acceptable salts”), and acompound, which has been alkylated or acylated at the 5′-position, or onthe purine or pyrimidine base (a type of “pharmaceutically acceptableprodrug”). Further, the modifications can affect the biological activityof the compound, in some cases increasing the activity over the parentcompound. This can easily be assessed by preparing the salt or prodrugand testing its antiviral activity according to the methods describedherein, or other methods known to those skilled in the art.

II. DEFINITIONS

The term alkyl, as used herein, unless otherwise specified, refers to asaturated straight, branched, or cyclic, primary, secondary, or tertiaryhydrocarbon of typically C₁ to C₁₀, and specifically includes methyl,trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl,t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl,cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl. The term includes both substituted and unsubstitutedalkyl groups. Moieties with which the alkyl group can be substituted areselected from the group consisting of hydroxyl, amino, alkylamino,arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate,phosphonic acid, phosphate, or phosphonate, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991, herebyincorporated by reference.

The term lower alkyl, as used herein, and unless otherwise specified,refers to a C₁ to C₄ saturated straight, branched, or if appropriate, acyclic (for example, cyclopropyl) alkyl group, including bothsubstituted and unsubstituted forms. Unless otherwise specificallystated in this application, when alkyl is a suitable moiety, lower alkylis preferred. Similarly, when alkyl or lower alkyl is a suitable moiety,unsubstituted alkyl or lower alkyl is preferred.

The term alkylamino or arylamino refers to an amino group that has oneor two alkyl or aryl substituents, respectively.

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis.

The term aryl, as used herein, and unless otherwise specified, refers tophenyl, biphenyl, or naphthyl, and preferably phenyl. The term includesboth substituted and unsubstituted moieties. The aryl group can besubstituted with one or more moieties selected from the group consistingof hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in Greene, et al.,Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991.

The term alkaryl or alkylaryl refers to an alkyl group with an arylsubstituent. The term aralkyl or arylalkyl refers to an aryl group withan alkyl substituent.

The term halo, as used herein, includes chloro, bromo, iodo, and fluoro.

The term purine or pyrimidine base includes, but is not limited to,adenine, N⁵-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl,aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine,N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, N⁶-thioalkyl purine, N²-alkylpurines, N²-alkyl-6-thiopurines,thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine,including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil,5-halouracil, including 5-fluorouracil, C⁵-alkylpyrimidines,C⁵-benzylpyrimidines, C⁵-halopyrimidines, C⁵-vinylpyrimidine,C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine,C⁵-amidopyrimidine, C⁵-cyanopyrimidine, C⁵-nitropyrimidine,C⁵-aminopyrimidine, N²-alkylpurines, N²-alkyl-6-thiopurines,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, and pyrazolo-pyrimidinyl. Purine bases include, butare not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine,and 6-chloropurine. Functional oxygen and nitrogen groups on the basecan be protected as necessary or desired. Suitable protecting groups arewell known to those skilled in the art, and include trimethylsilyl,dimethylhexylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl,trityl, alkyl groups, and acyl groups such as acetyl and propionyl,methanesulfonyl, and p-toluenesulfonyl. Alternatively, the purine orpyrimidine base can optionally substituted such that it forms a viableprodrug, which can be cleaved in vivo. Examples of appropriatesubstituents include acyl moiety, an amine or cyclopropyl (e.g.,2-amino, 2,6-diamino or cyclopropyl guanosine).

The term acyl refers to a carboxylic acid ester in which thenon-carbonyl moiety of the ester group is selected from straight,branched, or cyclic alkyl or lower alkyl, alkoxyalkyl includingmethoxymethyl, aralkyl including benzyl, aryloxyalkyl such asphenoxymethyl, aryl including phenyl optionally substituted withhalogen, C₁ to C₄ alkyl or C₁ to C₄ alkoxy, sulfonate esters such asalkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di ortriphosphate ester, trityl or monomethoxytrityl, substituted benzyl,trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. Arylgroups in the esters optimally comprise a phenyl group. The term “loweracyl” refers to an acyl group in which the non-carbonyl moiety is loweralkyl.

As used herein, the term “substantially free of” or “substantially inthe absence of” refers to a nucleoside composition that includes atleast 85 or 90% by weight, preferably 95% to 98% by weight, and evenmore preferably 99% to 100% by weight, of the designated enantiomer ofthat nucleoside. In a preferred embodiment, in the methods and compoundsof this invention, the compounds are substantially free of enantiomers.

Similarly, the term “isolated” refers to a nucleoside composition thatincludes at least 85 or 90% by weight, preferably 95% to 98% by weight,and even more preferably 99% to 100% by weight, of the nucleoside, theremainder comprising other chemical species or enantiomers.

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication. Thus, in a compound such as R″XYR″, wherein R″ is“independently carbon or nitrogen,” both R″ can be carbon, both R″ canbe nitrogen, or one R″ can be carbon and the other R″ nitrogen.

The term host, as used herein, refers to an unicellular or multicellularorganism in which the virus can replicate, including cell lines andanimals, and preferably a human. Alternatively, the host can be carryinga part of the flavivirus or pestivirus genome, whose replication orfunction can be altered by the compounds of the present invention. Theterm host specifically refers to infected cells, cells transfected withall or part of the flavivirus or pestivirus genome and animals, inparticular, primates (including chimpanzees) and humans. In most animalapplications of the present invention, the host is a human patient.Veterinary applications, in certain indications, however, are clearlyanticipated by the present invention (such as chimpanzees).

The term “pharmaceutically acceptable salt or prodrug” is usedthroughout the specification to describe any pharmaceutically acceptableform (such as an ester, phosphate ester, salt of an ester or a relatedgroup) of a nucleoside compound which; upon administration to a patient,provides the nucleoside compound. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids. Suitable salts include those derived fromalkali metals such as potassium and sodium, alkaline earth metals suchas calcium and magnesium, among numerous other acids well known in thepharmaceutical art. Pharmaceutically acceptable prodrugs refer to acompound that is metabolized, for example hydrolyzed or oxidized, in thehost to form the compound of the present invention. Typical examples ofprodrugs include compounds that have biologically labile protectinggroups on a functional moiety of the active compound. Prodrugs includecompounds that can be oxidized, reduced, aminated, deaminated,hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated,dealkylated, acylated, deacylated, phosphorylated, dephosphorylated toproduce the active compound. The compounds of this invention possessantiviral activity against flavivirus or pestivirus, or are metabolizedto a compound that exhibits such activity.

III. NUCLEOTIDE SALT OR PRODRUG FORMULATIONS

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate. Examples ofpharmaceutically acceptable salts are organic acid addition salts formedwith acids, which form a physiological acceptable anion, for example,tosylate, methanesulfonate, acetate, citrate, malonate, tartarate,succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate.Suitable inorganic salts may also be formed, including, sulfate,nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

Any of the nucleosides described herein can be administered as anucleotide prodrug to increase the activity, bioavailability, stabilityor otherwise alter the properties of the nucleoside. A number ofnucleotide prodrug ligands are known. In general, alkylation, acylationor other lipophilic modification of the mono, di or triphosphate of thenucleoside will increase the stability of the nucleotide. Examples ofsubstituent groups that can replace one or more hydrogens on thephosphate moiety are alkyl, aryl, steroids, carbohydrates, includingsugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jonesand N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of thesecan be used in combination with the disclosed nucleosides to achieve adesired effect.

The active nucleoside can also be provided as a 5′-phosphoether lipid ora 5′-ether lipid, as disclosed in the following references, which areincorporated by reference herein: Kucera, L. S., N. Iyer, E. Leake, A.Raben, Modest E. K., D. L. W., and C. Piantadosi, “Novelmembrane-interactive ether lipid analogs that inhibit infectious HIV-1production and induce defective virus formation,” AIDS Res. Hum. RetroViruses, 1990, 6, 491-501; Piantadosi, C., J. Marasco C. J., S. L.Morris-Natschke, K. L. Meyer, F. Gumus, J. R. Surles, K. S. Ishaq, L. S.Kucera, N. Iyer, C. A. Wallen, S. Piantadosi, and E. J. Modest,“Synthesis and evaluation of novel ether lipid nucleoside conjugates foranti-HIV activity,” J. Med. Chem., 1991, 34, 1408-1414; Hosteller, K.Y., D. D. Richman, D. A. Carson, L. M. Stuhmiller, G. M. T. van Wijk,and H. van den Bosch, “Greatly enhanced inhibition of humanimmunodeficiency virus type 1 replication in CEM and HT4-6C cells by3′-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of3,-deoxythymidine,” Antimicrob. Agents Chemother., 1992, 36, 2025-2029;Hosetler, K. Y., L. M. Stuhmiller, H. B. Lenting, H. van den Bosch, andD. D. Richman, “Synthesis and antiretroviral activity of phospholipidanalogs of azidothymidine and other antiviral nucleosides.” J. Biol.Chem., 1990, 265, 61127.

Nonlimiting examples of U.S. patents that disclose suitable lipophilicsubstituents that can be covalently incorporated into the nucleoside,preferably at the 5′-OH position of the nucleoside or lipophilicpreparations, include U.S. Pat. Nos. 5,149,794 (Sep. 22, 1992, Yatvin etal.); 5,194,654 (Mar. 16, 1993, Hostetler et al., 5,223,263 (Jun. 29,1993, Hostetler et al.); 5,256,641 (Oct. 26, 1993, Yatvin et al.);5,411,947 (May 2, 1995, Hostetler et al.); 5,463,092 (Oct. 31, 1995,Hostetler et al.); 5,543,389 (Aug. 6, 1996, Yatvin et al.); 5,543,390(Aug. 6, 1996, Yatvin et al.); 5,543,391 (Aug. 6, 1996, Yatvin et al.);and 5,554,728 (Sep. 10, 1996; Basava et al.), all of which areincorporated herein by reference. Foreign patent applications thatdisclose lipophilic substituents that can be attached to the nucleosidesof the present invention, or lipophilic preparations, include WO89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO94/26273, WO 96/15132, EP 0 350 287, EP 93917054.4, and WO 91/19721.

IV. COMBINATION AND ALTERNATION THERAPY

It has been recognized that drug-resistant variants of viruses canemerge after prolonged treatment with an antiviral agent. Drugresistance most typically occurs by mutation of a gene that encodes foran enzyme used in viral replication. The efficacy of a drug againstflavivirus or pestivirus infection can be prolonged, augmented, orrestored by administering the compound in combination or alternationwith a second, and perhaps third, antiviral compound that induces adifferent mutation from that caused by the principle drug.Alternatively, the pharmacokinetics, biodistribution or other parameterof the drug can be altered by such combination or alternation therapy.In general, combination therapy is typically preferred over alternationtherapy because it induces multiple simultaneous stresses on the virus.

Nonlimiting examples of antiviral agents that can be used in combinationor alternation with the compounds disclosed herein include:

(1) an interferon and/or ribavirin (Battaglia, A. M. et al., Ann.Pharmacother. 34:487-494, 2000); Berenguer, M. et al., Antivir. Ther.3(Suppl. 3):125-136, 1998);

(2) Substrate-based NS3 protease inhibitors (Attwood et al., Antiviralpeptide derivatives, PCT WO 98/22496, 1998; Attwood et al., AntiviralChemistry and Chemotherapy 10.259-273, 1999; Attwood et al., Preparationand use of amino acid derivatives as anti-viral agents, German PatentPublication DE 19914474; Tung et al. Inhibitors of serine proteases,particularly hepatitis C virus N83 protease, PCT WO 98/17679), includingalphaketoamides and hydrazinoureas, and inhibitors that terminate in anelectrophile such as a boronic acid or phosphonate. Llinas-Brunet et al,Hepatitis C inhibitor peptide analogues, PCT WO 99/07734.

(3) Non-substrate-based inhibitors such as2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. at al.,Biochemical and Biophysical Research Communications, 238:643-647, 1997;Sudo K. et al. Antiviral Chemistry and Chemotherapy 9:186, 1998),including RD3-4082 and RD3-4078, the former substituted on the amidewith a 14 carbon chain and the latter processing a para-phenoxyphenylgroup;

(4) Thiazolidine derivatives which show relevant inhibition in areverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5Bsubstrate (Sudo K. et al., Antiviral Research 32:9-18, 1996), especiallycompound RD-1-6250, possessing a fused cinnamoyl moiety substituted witha long alkyl chain, RD4 6205 and RD4 6193;

(5) Thiazolidines and benzanilides identified in Kakiuchi N. et al. J.EBS Letters 421:217-220; Takeshita N. et al. Analytical Biochemistry247:242-246, 1997;

(6) phenan-threnequinone possessing activity against protease in aSDS-PAGE and autoradiography assay isolated from the fermentationculture broth of Streptomyces sp., Sch 68631 (Chu M. et al., TetrahedronLetters 37:7229-7232, 1996), and Sch 351633, isolated from the fungusPenicillium griscofuluum, which demonstrates activity in a scintillationproximity assay (Chu M. et al., Bioorganic and Medicinal ChemistryLetters 9:1949-1952);

(7) Selective NS3 inhibitors based on the macromolecule elgin c,isolated from leech (Qasim M. A. et al., Biochemistry 36:1598-1607,1997);

(8) Helicase inhibitors (Diana G. D. et al., Compounds, compositions andmethods for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G.D. et al., Piperidine derivatives, pharmaceutical compositions thereofand their use in the treatment of hepatitis C, PCT WO 97/36554);

(9) Polymerase inhibitors such as nucleotide analogues, gliotoxin(Ferrari R. et al. Journal of Virology 73:1649-1654, 1999), and thenatural product cerulenin (Lohmann V. et al., Virology 249:108-118,1998);

(10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN)complementary to sequence stretches in the 5′ non-coding region (NCR) ofthe virus (Alt M. et al., Hepatology 22:707-717, 1995), or nucleotides326-348 comprising the 3′ end of the NCR and nucleotides 371-388 locatedin the core coding region of the IICV RNA (Alt M. et al., Archives ofVirology 142:589-599, 1997; Galderisi U. et al., Journal of CellularPhysiology 181:251-257, 1999);

(11) Inhibitors of IRES-dependent translation (Ikeda N et al., Agent forthe prevention and treatment of hepatitis C, Japanese Patent PublicationJP-08268890; Kai Y. et al. Prevention and treatment of viral diseases,Japanese Patent Publication JP-10101591);

(12) Nuclease-resistant ribozymes. (Maccjak D. J. et al., Hepatology 30abstract 995, 1999); and

(13) Other miscellaneous compounds including 1-amino-alkylcyclohexanes(U.S. Pat. No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Pat. No.5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S.Pat. No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids(U.S. Pat. No. 5,846,964 to Ozeki et al.),N-(phosphonoacetyl)-L-aspartic acid, (U.S. Pat. No. 5,830,905 to Dianaet al.), benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana etal.), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang etal.), 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687 to Yarchoan et al),and benzimidazoles (U.S. Pat. No. 5,891,874 to Colacino et al.).

V. PHARMACEUTICAL COMPOSITIONS

Host, including humans, infected with flavivirus or pestivirus, or agene fragment thereof can be treated by administering to the patient aneffective amount of the active compound or a pharmaceutically acceptableprodrug or salt thereof in the presence of a pharmaceutically acceptablecarrier or diluent. The active materials can be administered by anyappropriate route, for example, orally, parenterally, intravenously,intradermally, subcutaneously, or topically, in liquid or solid form.

A preferred dose of the compound for flavivirus or pestivirus infectionwill be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg,of body weight per day, more generally 0.1 to about 100 mg per kilogrambody weight of the recipient per day. The effective dosage range of thepharmaceutically acceptable salts and prodrugs can be calculated basedon the weight of the parent nucleoside to be delivered. If the salt orprodrug exhibits activity in itself, the effective dosage can beestimated as above using the weight of the salt or prodrug, or by othermeans known to those skilled in the art.

The compound is conveniently administered in unit any suitable dosageform, including but not limited to one containing 7 to 3000 mg,preferably 70 to 1400 mg of active ingredient per unit dosage form. Aoral dosage of 50-1000 mg is usually convenient.

Ideally the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.2 to 70 μM,preferably about 1.0 to 10 μM. This may be achieved, for example, by theintravenous injection of a 0.1 to 5% solution of the active ingredient,optionally in saline, or administered as a bolus of the activeingredient.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It, is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcomposition. The active ingredient may be administered at once, or maybe divided into a number of smaller doses to be administered at varyingintervals of time.

A preferred mode of administration of the active compound is oral. Oralcompositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring. When the dosageunit form is a capsule, it can contain, in addition to material of theabove type, a liquid carrier such as a fatty oil. In addition, dosageunit forms can contain various other materials which modify the physicalform of the dosage unit, for example, coatings of sugar, shellac, orother enteric agents.

The compound can be administered as a component of an elixir,suspension, syrup, wafer, chewing gum or the like. A syrup may contain,in addition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors.

The compound or a pharmaceutically acceptable prodrug or salts thereofcan also be mixed with other active materials that do not impair thedesired action, or with materials that supplement the desired action,such as antibiotics, antifungals, anti-inflammatories, or otherantivirals, including other nucleoside compounds. Solutions orsuspensions used for parenteral, intradermal, subcutaneous, or topicalapplication can include the following components: a sterile diluent suchas water for injection, saline solution, fixed oils, polyethyleneglycols, glycerine, propylene glycol or other synthetic solvents;antibacterial agents such as benzyl alcohol or methyl parabens;antioxidants such as ascorbic acid or sodium bisulfate; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parental preparation can be enclosed inampoules, disposable syringes or multiple dose vials made of glass orplastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation.

Liposomal suspensions (including liposomes targeted to infected cellswith monoclonal antibodies to viral antigens) are also preferred aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art, for example, as described inU.S. Pat. No. 4,522,811 (which is incorporated herein by reference inits entirety). For example, liposome formulations may be prepared bydissolving appropriate lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent that is thenevaporated, leaving behind a thin film of dried lipid on the surface ofthe container. An aqueous solution of the active compound or itsmonophosphate, diphosphate, and/or triphosphate derivatives is thenintroduced into the container. The container is then swirled by hand tofree lipid material from the sides of the container and to disperselipid aggregates, thereby forming the liposomal suspension.

VI. PROCESSES FOR THE PREPARATION OF ACTIVE COMPOUNDS

The nucleosides of the present invention can be synthesized by any meansknown in the art. In particular, the synthesis of the presentnucleosides can be achieved by either alkylating the appropriatelymodified sugar, followed by glycosylation or glycosylation followed byalkylation of the nucleoside. The following non-limiting embodimentsillustrate some general methodology to obtain the nucleosides of thepresent invention.

A. General Synthesis of 1′-C-Branched Nucleosides

1% C-Branched ribonucleosides of the following structure:

wherein BASE is a purine or pyrimidine base as defined herein;R⁷ and R⁹ are independently hydrogen, OR², hydroxy, alkyl (includinglower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl),—C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(loweralkyl), —O(alkenyl), chlorine, bromine, iodine, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂;R⁸ and R¹⁰ are independently H, alkyl (including lower alkyl), chlorine,bromine or iodine;alternatively, R⁷ and R⁹, R⁷ and R¹⁰, R⁸ and R⁹, or R⁸ and R¹⁰ can cometogether to form a pi bond;R¹ and R² are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹ is independently H or phosphate;R⁶ is an alkyl, halogeno-alkyl (i.e. CF₃), alkenyl, or alkynyl (i.e.allyl); and

X is O, S, SO₂ or CH₂

can be prepared by one of the following general methods.1) Modification from the Lactone

The key starting material for this process is an appropriatelysubstituted lactone. The lactone can be purchased or can be prepared byany known means including standard epimerization, substitution andcyclization techniques. The lactone can be optionally protected with asuitable protecting group, preferably with an acyl or silyl group, bymethods well known to those skilled in the art, as taught by Greene etal. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991. The protected lactone can then be coupled with a suitablecoupling agent, such as an organometallic carbon nucleophile, such as aGrignard reagent, an organolithium, lithium dialkylcopper or R⁶—SiMe₃ inTBAF with the appropriate non-protic solvent at a suitable temperature,to give the 1′-alkylated sugar.

The optionally activated sugar can then be coupled to the BASE bymethods well known to those skilled in the art, as taught by TownsendChemistry of Nucleosides and Nucleotides, Plenum Press, 1994. Forexample, an acylated sugar can be coupled to a silylated base with alewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 1′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 1. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

2. Alternative Method for the Preparation of 1′-C-Branched Nucleosides

The key starting material for this process is an appropriatelysubstituted hexose. The hexose can be purchased or can be prepared byany known means including standard epimerization (e.g. via alkalinetreatment), substitution and coupling techniques. The hexose can beselectively protected to give the appropriate hexa-furanose, as taughtby Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press,1994.

The 1′-hydroxyl can be optionally activated to a suitable leaving groupsuch as an acyl group or a halogen via acylation or halogenation,respectively. The optionally activated sugar can then be coupled to theBASE by methods well known to those skilled in the art, as taught byTownsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994.For example, an acylated sugar can be coupled to a silylated base with alewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature. Alternatively, a halo-sugar can be coupled to a silylatedbase with the presence of trimethylsilyltriflate.

The 1′-CH₂—OH, if protected, can be selectively deprotected by methodswell known in the art. The resultant primary hydroxyl can befunctionalized to yield various C-branched nucleosides. For example, theprimary hydroxyl can be reduced to give the methyl, using a suitablereducing agent. Alternatively, the hydroxyl can be activated prior toreduction to facilitate the reaction; i.e. via the Barton reduction. Inan alternate embodiment, the primary hydroxyl can be oxidized to thealdehyde, then coupled with a carbon nucleophile, such as a Grignardreagent, an organolithium, lithium dialkylcopper or R⁶—SiMe₃ in TBAFwith the appropriate non-protic solvent at a suitable temperature.

In a particular embodiment, the 1′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 2. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

In addition, the L-enantiomers corresponding to the compounds of theinvention can be prepared following the same general methods (1 or 2),beginning with the corresponding L-sugar or nucleoside L-enantiomer asstarting material.

B. General Synthesis of 2′-C-Branched Nucleosides

2′-C-Branched ribonucleosides of the following structure:

wherein BASE is a purine or pyrimidine base as defined herein;R⁷ and R⁹ are independently hydrogen, OR², hydroxy, alkyl (includinglower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl),—C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(loweralkyl), —O(alkenyl), chlorine, bromine, iodine, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂;R¹⁰ is H, alkyl (including lower alkyl), chlorine, bromine or iodine;alternatively, R⁷ and R⁹, or R⁷ and R¹⁰ can come together to form a pibond;R¹ and R² are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹ is independently H or phosphate;R⁶ is an alkyl, halogeno-alkyl (i.e. CF₃), alkenyl, or alkynyl (i.e.allyl); and

X is O, S, SO₂ or CH₂

can be prepared by one of the following general methods.I. Glycosylation of the Nucleobase with an Appropriately Modified Sugar

The key starting material for this process is an appropriatelysubstituted sugar with a 2′-OH and 2′-H, with the appropriate leavinggroup (LG), for example an acyl group or a halogen. The sugar can bepurchased or can be prepared by any known means including standardepimerization, substitution, oxidation and reduction techniques. Thesubstituted sugar can then be oxidized with the appropriate oxidizingagent in a compatible solvent at a suitable temperature to yield the2′-modified sugar. Possible oxidizing agents are Jones reagent (amixture of chromic acid and sulfuric acid), Collins's reagent(dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate),pyridinium dichromate, acid dichromate, potassium permanganate, MnO₂,ruthenium tetroxide, phase transfer catalysts such as chromic acid orpermanganate supported on a polymer, Cl₂-pyridine, H₂O₂-ammoniummolybdate, NaBrO₂—CAN, NaOCl in HOAc, copper chromite, copper oxide,Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent(aluminum t-butoxide with another ketone) and N-bromosuccinimide.

Then coupling of an organometallic carbon nucleophile, such as aGrignard reagent, an organolithium, lithium dialkylcopper or R⁶—SiMe₃ inTBAF with the ketone with the appropriate non-protic solvent at asuitable temperature, yields the 2′-alkylated sugar. The alkylated sugarcan be optionally protected with a suitable protecting group, preferablywith an acyl or silyl group, by methods well known to those skilled inthe art, as taught by Greene et al. Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991.

The optionally protected sugar can then be coupled to the BASE bymethods well known to those skilled in the art, as taught by TownsendChemistry of Nucleosides and Nucleotides, Plenum Press, 1994. Forexample, an acylated sugar can be coupled to a silylated base with alewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature. Alternatively, a halo-sugar can be coupled to a silylatedbase with the presence of trimethylsilyltriflate.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 2′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 3. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

2. Modification of a Pre-Formed Nucleoside

The key starting material for this process is an appropriatelysubstituted nucleoside with a 2′-OH and 2′-H. The nucleoside can bepurchased or can be prepared by any known means including standardcoupling techniques. The nucleoside can be optionally protected withsuitable protecting groups, preferably with acyl or silyl groups, bymethods well known to those skilled in the art, as taught by Greene etal. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991.

The appropriately protected nucleoside can then be oxidized with theappropriate oxidizing agent in a compatible solvent at a suitabletemperature to yield the 2′-modified sugar. Possible oxidizing agentsare Jones reagent (a mixture of chromic acid and sulfuric acid),Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridiniumchlorochromate), pyridinium dichromate, acid dichromate, potassiumpermanganate, MnO₂, ruthenium tetroxide, phase transfer catalysts suchas chromic acid or permanganate supported on a polymer, Cl₂-pyridine,H₂O₂-ammonium molybdate, NaBrO₂—CAN, NaOCl in HOAc, copper chromite,copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verleyreagent (aluminum t-butoxide with another ketone) andN-bromosuccinimide.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled, in the art, as taught by GreeneGreene el al. ProtectiveGroups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 2′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 4. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

In another embodiment of the invention, the L-enantiomers are desired.Therefore, the L-enantiomers can be corresponding to the compounds ofthe invention can be prepared following the same foregoing generalmethods, beginning with the corresponding L-sugar or nucleosideL-enantiomer as starting material.

C. General Synthesis of 3′-C-Branched Nucleosides

3′-C-Branched ribonucleosides of the following structure:

wherein BASE is a purine or pyrimidine base as defined herein;R⁷ and R⁹ are independently hydrogen, OR², hydroxy, alkyl (includinglower alkyl), azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl),—C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(loweralkyl), —O(alkenyl), chlorine, bromine, iodine, NO₂, NH₂, —NH(loweralkyl), —NH(acyl), —N(lower alkyl)₂, —N(acyl)₂;R⁸ is H, alkyl (including lower alkyl), chlorine, bromine or iodine;alternatively, R⁷ and R⁹, or R⁸ and R⁹ can come together to form a pibond;R¹ and R² are independently H; phosphate (including monophosphate,diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl(including lower acyl); alkyl (including lower alkyl); sulfonate esterincluding alkyl or arylalkyl sulfonyl including methanesulfonyl andbenzyl, wherein the phenyl group is optionally substituted with one ormore substituents as described in the definition of aryl given herein; alipid, including a phospholipid; an amino acid; a carbohydrate; apeptide; a cholesterol; or other pharmaceutically acceptable leavinggroup which when administered in vivo is capable of providing a compoundwherein R¹ is independently H or phosphate;R⁶ is an alkyl, halogeno-alkyl (i.e. CF₃), alkenyl, or alkynyl (i.e.allyl); and

X is O, S, SO₂ or CH₂

can be prepared by one of the following general methods.1 Glycosylation of the Nucleobase with an Appropriately Modified Sugar

The key starting material for this process is an appropriatelysubstituted sugar with a 3′-OH and 3′-H, with the appropriate leavinggroup (LG), for example an acyl group or a halogen. The sugar can bepurchased or can be prepared by any known means including standardepimerization, substitution, oxidation and reduction techniques. Thesubstituted sugar can then be oxidized with the appropriate oxidizingagent in a compatible solvent at a suitable temperature to yield the3′-modified sugar. Possible oxidizing agents are Jones reagent (amixture of chromic acid and sulfuric acid), Collins's reagent(dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate),pyridinium dichromate, acid dichromate, potassium permanganate, MnO₂,ruthenium tetroxide, phase transfer catalysts such as chronic acid orpermanganate supported on a polymer, Cl₂-pyridine, H₂O₂-ammoniummolybdate, NaBrO₂—CAN, NaOCl in HOAc, copper chromite, copper oxide,Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent(aluminum t-butoxide with another ketone) and N-bromosuccinimide.

Then coupling of an organometallic carbon nucleophile, such as aGrignard reagent, an organolithium, lithium dialkylcopper or R⁶—SiMe₃ inTBAF with the ketone with the appropriate non-protic solvent at asuitable temperature, yields the 3′-C-branched sugar. The 3′-C-branchedsugar can be optionally protected with a suitable protecting group,preferably with an acyl or silyl group, by methods well known to thoseskilled in the art, as taught by Greene et al. Protective Groups inOrganic Synthesis, John Wiley and Sons, Second Edition, 1991.

The optionally protected sugar can then be coupled to the BASE bymethods well known to those skilled in the art, as taught by TownsendChemistry of Nucleosides and Nucleotides, Plenum Press, 1994. Forexample, an acylated sugar can be coupled to a silylated base with alewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature. Alternatively, a halo-sugar can be coupled to a silylatedbase with the presence of trimethylsilyltriflate.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 3′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 5. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

2. Modification of a Pre-Formed Nucleoside

The key starting material for this process is an appropriatelysubstituted nucleoside with a 3′-OH and 3′-H. The nucleoside can bepurchased or can be prepared by any known means including standardcoupling techniques. The nucleoside can be optionally protected withsuitable protecting groups, preferably with acyl or silyl groups, bymethods well known to those skilled in the art, as taught by Greene etal. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991.

The appropriately protected nucleoside can then be oxidized with theappropriate oxidizing agent in a compatible solvent at a suitabletemperature to yield the 2′-modified sugar. Possible oxidizing agentsare Jones reagent (a mixture of chromic acid and sulfuric acid),Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridiniumchlorochromate), pyridinium dichromate, acid dichromate, potassiumpermanganate, MnO₂, ruthenium tetroxide, phase transfer catalysts suchas chromic acid or permanganate supported on a polymer, Cl₂-pyridine,H₂O₂-ammonium molybdate, NaBrO₂—CAN, NaOCl in HOAc, copper chromite,copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verleyreagent (aluminum t-butoxide with another ketone) andN-bromosuccinimide.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 3′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 6. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

In another embodiment of the invention, the L-enantiomers are desired.Therefore, the L-enantiomers can be corresponding to the compounds ofthe invention can be prepared following the same foregoing generalmethods, beginning with the corresponding L-sugar or nucleosideL-enantiomer as starting material.

EXAMPLES Example 1 Preparation of r-C-methylriboadenine via6-amino-9-(1-deoxy-β-D-psicofuranosyl)purine

The title compound could also be prepared according to a publishedprocedure (J. Farkas, and F. Sorm, “Nucleic acid components and theiranalogues. XCIV. Synthesis of6-amino-9-(1-deoxy-β-D-psicofuranosyl)purine” Collect. Czech. Chem.Commun. 1967, 32, 2663-2667; J. Farkas”, Collect. Czech. Chem. Commun.1966, 31, 1535) (Scheme 7).

In a similar manner, but using the appropriate sugar and pyrimidine orpurine bases, the following nucleosides of Formula I are prepared.

(I)

R¹ R² R³ X¹ X² Y H H H H H H H H H H H NH₂ H H H H H NH-cyclopropyl H HH H H NH-methyl H H H H H NH-ethyl H H H H H NH-acetyl H H H H H OH H HH H H OMe H H H H H OEt H H H H H O-cyclopropyl H H H H H O-acetyl H H HH H SH H H H H H SMe H H H H H SEt H H H H H S-cyclopropyl H H H H H F HH H H H Cl H H H H H Br H H H H H I monophosphate H H H H NH₂monophosphate H H H H NH-acetyl monophosphate H H H H NH-cyclopropylmonophosphate H H H H NH-methyl monophosphate H H H H NH-ethylmonophosphate H H H H OH monophosphate H H H H O-acetyl monophosphate HH H H OMe monophosphate H H H H OEt monophosphate H H H H O-cyclopropylmonophosphate H H H H SH monophosphate H H H H SMe monophosphate H H H HSEt monophosphate H H H H S-cyclopropyl monophosphate H H H H Fmonophosphate H H H H Cl monophosphate H H H H Br monophosphate H H H HI diphosphate H H H H NH₂ diphosphate H H H H NH-acetyl diphosphate H HH H NH-cyclopropyl diphosphate H H H H NH-methyl diphosphate H H H HNH-ethyl diphosphate H H H H OH diphosphate H H H H O-acetyl diphosphateH H H H OMe diphosphate H H H H OEt diphosphate H H H H O-cyclopropyldiphosphate H H H H SH diphosphate H H H H SMe diphosphate H H H H SEtdiphosphate H H H H S-cyclopropyl diphosphate H H H H F diphosphate H HH H Cl diphosphate H H H H Br diphosphate H H H H I triphosphate H H H HNH₂ triphosphate H H H H NH-acetyl triphosphate H H H H NH-cyclopropyltriphosphate H H H H NH-methyl triphosphate H H H H NH-ethyltriphosphate H H H H OH triphosphate H H H H OMe triphosphate H H H HOEt triphosphate H H H H O-cyclopropyl triphosphate H H H H O-acetyltriphosphate H H H H SH triphosphate H H H H SMe triphosphate H H H HSEt triphosphate H H H H S-cyclopropyl triphosphate H H H H Ftriphosphate H H H H Cl triphosphate H H H H Br triphosphate H H H H Imonophosphate monophosphate monophosphate H H NH₂ monophosphatemonophosphate monophosphate H H NH-cyclopropyl monophosphatemonophosphate monophosphate H H OH monophosphate monophosphatemonophosphate H H F monophosphate monophosphate monophosphate H H Cldiphosphate diphosphate diphosphate H H NH₂ diphosphate diphosphatediphosphate H H NH-cyclopropyl diphosphate diphosphate diphosphate H HOH diphosphate diphosphate diphosphate H H F diphosphate diphosphatediphosphate H H Cl triphosphate triphosphate triphosphate H H NH₂triphosphate triphosphate triphosphate H H NH-cyclopropyl triphosphatetriphosphate triphosphate H H OH triphosphate triphosphate triphosphateH H F triphosphate triphosphate triphosphate H H Cl H H H F H NH₂ H H HF H NH-cyclopropyl H H H F H OH H H H F H F H H H F H Cl H H H Cl H NH₂H H H Cl H NH-cyclopropyl H H H Cl H OH H H H Cl H F H H H Cl H Cl H H HBr H NH₂ H H H Br H NH-cyclopropyl H H H Br H OH H H H Br H F H H H Br HCl H H H NH₂ H NH₂ H H H NH₂ H NH-cyclopropyl H H H NH₂ H OH H H H NH₂ HF H H H NH₂ H Cl H H H SH H NH₂ H H H SH H NH-cyclopropyl H H H SH H OHH H H SH H F H H H SH H Cl acetyl H H H H NH₂ acetyl H H H HNH-cyclopropyl acetyl H H H H OH acetyl H H H H F acetyl H H H H Clacetyl H H F H NH₂ acetyl H H F H NH-cyclopropyl acetyl H H F H OHacetyl H H F H F acetyl H H F H Cl H acetyl acetyl H H NH₂ H acetylacetyl H H NH-cyclopropyl H acetyl acetyl H H OH H acetyl acetyl H H F Hacetyl acetyl H H Cl acetyl acetyl acetyl H H NH₂ acetyl acetyl acetyl HH NH-cyclopropyl acetyl acetyl acetyl H H OH acetyl acetyl acetyl II H Facetyl acetyl acetyl H H Cl monophosphate acetyl acetyl H H NH₂monophosphate acetyl acetyl H H NH-cyclopropyl monophosphate acetylacetyl H H OH monophosphate acetyl acetyl H H F monophosphate acetylacetyl H H Cl diphosphate acetyl acetyl H H NH₂ diphosphate acetylacetyl H H NH-cyclopropyl diphosphate acetyl acetyl H H OH diphosphateacetyl acetyl H H F diphosphate acetyl acetyl H H Cl triphosphate acetylacetyl H H NH₂ triphosphate acetyl acetyl H H NH-cyclopropyltriphosphate acetyl acetyl H H OH triphosphate acetyl acetyl H H Ftriphosphate acetyl acetyl H H Cl H H H H NH₂ H H H H H NH₂ NH₂ H H H HNH₂ NH-cyclopropyl H H H H NH₂ NH-methyl H H H H NH₂ NH-ethyl H H H HNH₂ NH-acetyl H H H H NH₂ OH H H H H NH₂ OMe H H H H NH₂ OEt H H H H NH₂O-cyclopropyl H H H H NH₂ O-acetyl H H H H NH₂ SH H H H H NH₂ SMe H H HH NH₂ SEt H H H H NH₂ S-cyclopropyl H H H H NH₂ F H H H H NH₂ Cl H H H HNH₂ Br H H H H NH₂ I monophosphate H H H NH₂ NH₂ monophosphate H H H NH₂NH-acetyl monophosphate H H H NH₂ NH-cyclopropyl monophosphate H H H NH₂NH-methyl monophosphate H H H NH₂ NH-ethyl monophosphate H H H NH₂ OHmonophosphate H H H NH₂ O-acetyl monophosphate H H H NH₂ OMemonophosphate H H H NH₂ OEt monophosphate H H H NH₂ O-cyclopropylmonophosphate H H H NH₂ SH monophosphate H H H NH₂ SMe monophosphate H HH NH₂ SEt monophosphate H H H NH₂ S-cyclopropyl monophosphate H H H NH₂F monophosphate H H H NH₂ Cl monophosphate H H H NH₂ Br monophosphate HH H NH₂ I diphosphate H H H NH₂ NH₂ diphosphate H H H NH₂ NH-acetyldiphosphate H H H NH₂ NH-cyclopropyl diphosphate H H H NH₂ NH-methyldiphosphate H H H NH₂ NH-ethyl diphosphate H H H NH₂ OH diphosphate H HH NH₂ O-acetyl diphosphate H H H NH₂ OMe diphosphate H H H NH₂ OEtdiphosphate H H H NH₂ O-cyclopropyl diphosphate H H H NH₂ SH diphosphateH H H NH₂ SMe diphosphate H H H NH₂ SEt diphosphate H H H NH₂S-cyclopropyl diphosphate H H H NH₂ F diphosphate H H H NH₂ Cldiphosphate H H H NH₂ Br diphosphate H H H NH₂ I triphosphate H H H NH₂NH₂ triphosphate H H H NH₂ NH-acetyl triphosphate H H H NH₂NH-cyclopropyl triphosphate H H H NH₂ NH-methyl triphosphate H H H NH₂NH-ethyl triphosphate H H H NH₂ OH triphosphate H H H NH₂ OMetriphosphate H H H NH₂ OEt triphosphate H H H NH₂ O-cyclopropyltriphosphate H H H NH₂ O-acetyl triphosphate H H H NH₂ SH triphosphate HH H NH₂ SMe triphosphate H H H NH₂ SEt triphosphate H H H NH₂S-cyclopropyl triphosphate H H H NH₂ F triphosphate H H H NH₂ Cltriphosphate H H H NH₂ Br triphosphate H H H NH₂ I monophosphatemonophosphate monophosphate H NH₂ NH₂ monophosphate monophosphatemonophosphate H NH₂ NH-cyclopropyl monophosphate monophosphatemonophosphate H NH₂ OH monophosphate monophosphate monophosphate H NH₂ Fmonophosphate monophosphate monophosphate H NH₂ Cl diphosphatediphosphate diphosphate H NH₂ NH₂ diphosphate diphosphate diphosphate HNH₂ NH-cyclopropyl diphosphate diphosphate diphosphate H NH₂ OHdiphosphate diphosphate diphosphate H NH₂ F diphosphate diphosphatediphosphate H NH₂ Cl triphosphate triphosphate triphosphate H NH₂ NH₂triphosphate triphosphate triphosphate H NH₂ NH-cyclopropyl triphosphatetriphosphate triphosphate H NH₂ OH triphosphate triphosphatetriphosphate H NH₂ F triphosphate triphosphate triphosphate H NH₂ Cl H HH F NH₂ NH₂ H H H F NH₂ NH-cyclopropyl H H H F NH₂ OH H H H F NH₂ F H HH F NH₂ Cl H H H Cl NH₂ NH₂ H H H Cl NH₂ NH-cyclopropyl H H H Cl NH₂ OHH H H Cl NH₂ F H H H Cl NH₂ Cl H H H Br NH₂ NH₂ H H H Br NH₂NH-cyclopropyl H H H Br NH₂ OH H H H Br NH₂ F H H H Br NH₂ Cl H H H NH₂NH₂ NH₂ H H H NH₂ NH₂ NH-cyclopropyl H H H NH₂ NH₂ OH H H H NH₂ NH₂ F HH H NH₂ NH₂ Cl H H H SH NH₂ NH₂ H H H SH NH₂ NH-cyclopropyl H H H SH NH₂OH H H H SH NH₂ F H H H SH NH₂ Cl acetyl H H H NH₂ NH₂ acetyl H H H NH₂NH-cyclopropyl acetyl H H H NH₂ OH acetyl H H H NH₂ F acetyl H H H NH₂Cl acetyl H H F NH₂ NH₂ acetyl H H F NH₂ NH-cyclopropyl acetyl H H F NH₂OH acetyl H H F NH₂ F acetyl H H F NH₂ Cl H acetyl acetyl H NH₂ NH₂ Hacetyl acetyl H NH₂ NH-cyclopropyl H acetyl acetyl H NH₂ OH H acetylacetyl H NH₂ F H acetyl acetyl H NH₂ Cl acetyl acetyl acetyl H NH₂ NH₂acetyl acetyl acetyl H NH₂ NH-cyclopropyl acetyl acetyl acetyl H NH₂ OHacetyl acetyl acetyl H NH₂ F acetyl acetyl acetyl H NH₂ Cl monophosphateacetyl acetyl H NH₂ NH₂ monophosphate acetyl acetyl H NH₂ NH-cyclopropylmonophosphate acetyl acetyl H NH₂ OH monophosphate acetyl acetyl H NH₂ Fmonophosphate acetyl acetyl H NH₂ Cl diphosphate acetyl acetyl H NH₂ NH₂diphosphate acetyl acetyl H NH₂ NH-cyclopropyl diphosphate acetyl acetylH NH₂ OH diphosphate acetyl acetyl H NH₂ F diphosphate acetyl acetyl HNH₂ Cl triphosphate acetyl acetyl H NH₂ NH₂ triphosphate acetyl acetyl HNH₂ NH-cyclopropyl triphosphate acetyl acetyl H NH₂ OH triphosphateacetyl acetyl H NH₂ F triphosphate acetyl acetyl H NH₂ Cl H H H H Cl H HH H H Cl H H H H H Cl NH₂ H H H H Cl NH-cyclopropyl H H H H Cl NH-methylH H H H Cl NH-ethyl H H H H Cl NH-acetyl H H H H Cl OH H H H H Cl OMe HH H H Cl OEt H H H H Cl O-cyclopropyl H H H H Cl O-acetyl H H H H Cl SHH H H H Cl SMe H H H H Cl SEt H H H H Cl S-cyclopropyl monophosphate H HH Cl NH₂ monophosphate H H H Cl NH-acetyl monophosphate H H H ClNH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H ClNH-ethyl monophosphate H H H Cl OH monophosphate H H H Cl O-acetylmonophosphate H H H Cl OMe monophosphate H H H Cl OEt monophosphate H HH Cl O-cyclopropyl monophosphate H H H Cl SH monophosphate H H H Cl SMemonophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyldiphosphate H H H Cl NH₂ diphosphate H H H Cl NH-acetyl diphosphate H HH Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H ClNH-ethyl diphosphate H H H Cl OH diphosphate H H H Cl O-acetyldiphosphate H H H Cl OMe diphosphate H H H Cl OEt diphosphate H H H ClO-cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMediphosphate H H H Cl SEt diphosphate H H H Cl S-cyclopropyl triphosphateH H H Cl NH₂ triphosphate H H H Cl NH-acetyl triphosphate H H H ClNH-cyclopropyl triphosphate H H H Cl NH-methyl triphosphate H H H ClNH-ethyl triphosphate H H H Cl OH triphosphate H H H Cl OMe triphosphateH H H Cl OEt triphosphate H H H Cl O-cyclopropyl triphosphate H H H ClO-acetyl triphosphate H H H Cl SH triphosphate H H H Cl SMe triphosphateH H H Cl SEt triphosphate H H H Cl S-cyclopropyl monophosphatemonophosphate monophosphate H Cl NH₂ monophosphate monophosphatemonophosphate H Cl NH-cyclopropyl monophosphate monophosphatemonophosphate H Cl OH diphosphate diphosphate diphosphate H Cl NH₂diphosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphatediphosphate diphosphate H Cl OH triphosphate triphosphate triphosphate HCl NH₂ triphosphate triphosphate triphosphate H Cl NH-cyclopropyltriphosphate triphosphate triphosphate H Cl OH H H H F Cl NH₂ H H H F ClNH-cyclopropyl H H H F Cl OH H H H Cl Cl NH₂ H H H Cl Cl NH-cyclopropylH H H Cl Cl OH H H H Br Cl NH₂ H H H Br Cl NH-cyclopropyl H H H Br Cl OHH H H NH₂ Cl NH₂ H H H NH₂ Cl NH-cyclopropyl H H H NH₂ Cl OH H H H SH ClNH₂ H H H SH Cl NH-cyclopropyl H H H SH Cl OH acetyl H H H Cl NH₂ acetylH H H Cl NH-cyclopropyl acetyl H H H Cl OH acetyl H H F Cl NH₂ acetyl HH F Cl NH-cyclopropyl acetyl H H F Cl OH H acetyl acetyl H Cl NH₂ Hacetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H Cl OH acetyl acetylacetyl H Cl NH₂ acetyl acetyl acetyl H Cl NH-cyclopropyl acetyl acetylacetyl H Cl OH monophosphate acetyl acetyl H Cl NH₂ monophosphate acetylacetyl H Cl NH-cyclopropyl monophosphate acetyl acetyl H Cl OHdiphosphate acetyl acetyl H Cl NH₂ diphosphate acetyl acetyl H ClNH-cyclopropyl diphosphate acetyl acetyl H Cl OH triphosphate acetylacetyl H Cl NH₂ triphosphate acetyl acetyl H Cl NH-cyclopropyltriphosphate acetyl acetyl H Cl OH H H H H Cl NH₂ H H H H ClNH-cyclopropyl H H H H Cl OH H H H H Br NH₂ H H H H Br NH-cyclopropyl HH H H Br OH

Alternatively, the following nucleosides of Formula IV are prepared,using the appropriate sugar and pyrimidine or purine bases.

(IV)

R¹ R² R³ X¹ Y H H H H H H H H H NH₂ H H H H NH-cyclopropyl H H H HNH-methyl H H H H NH-ethyl H H H H NH-acetyl H H H H OH H H H H OMe H HH H OEt H H H H O-cyclopropyl H H H H O-acetyl H H H H SH H H H H SMe HH H H SEt H H H H S-cyclopropyl monophosphate H H H NH₂ monophosphate HH H NH-acetyl monophosphate H H H NH-cyclopropyl monophosphate H H HNH-methyl monophosphate H H H NH-ethyl monophosphate H H H OHmonophosphate H H H O-acetyl monophosphate H H H OMe monophosphate H H HOEt monophosphate H H H O-cyclopropyl monophosphate H H H SHmonophosphate H H H SMe monophosphate H H H SEt monophosphate H H HS-cyclopropyl diphosphate H H H NH₂ diphosphate H H H NH-acetyldiphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl diphosphateH H H NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyldiphosphate H H H OMe diphosphate H H H OEt diphosphate H H HO-cycopropyl diphosphate H H H SH diphosphate H H H SMe diphosphate H HH SEt diphosphate H H H S-cycopropyl triphosphate H H H NH₂ triphosphateH H H NH-acetyl triphosphate H H H NH-cyclopropyl triphosphate H H HNH-methyl triphosphate H H H NH-ethyl triphosphate H H H OH triphosphateH H H OMe triphosphate H H H OEt triphosphate H H H O-cyclopropyltriphosphate H H H O-acetyl triphosphate H H H SH triphosphate H H H SMetriphosphate H H H SEt triphosphate H H H S-cyclopropyl monophosphatemonophosphate monophosphate H NH₂ monophosphate monophosphatemonophosphate H NH-cyclopropyl monophosphate monophosphate monophosphateH OH diphosphate diphosphate diphosphate H NH₂ diphosphate diphosphatediphosphate H NH-cyclopropyl diphosphate diphosphate diphosphate H OHtriphosphate triphosphate triphosphate H NH₂ triphosphate triphosphatetriphosphate H NH-cyclopropyl triphosphate triphosphate triphosphate HOH H H H F NH₂ H H H F NH-cycopropyl H H H F OH H H H Cl NH₂ H H H ClNH-cyclopropyl H H H Cl OH H H H Br NH₂ H H H Br NH-cyclopropyl H H H BrOH H H H NH₂ NH₂ H H H NH₂ NH-cyclopropyl H H H NH₂ OH H H H SH NH₂ H HH SH NH-cyclopropyl H H H SH OH acetyl H H H NH₂ acetyl H H HNH-cyclopropyl acetyl H H H OH acetyl H H F NH₂ acetyl H H FNH-cyclopropyl acetyl H H F OH H acetyl acetyl H NH₂ H acetyl acetyl HNH-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H NH₂ acetylacetyl acetyl H NH-cyclopropyl acetyl acetyl acetyl H OH monophosphateacetyl acetyl H NH₂ monophosphate acetyl acetyl H NH-cyclopropylmonophosphate acetyl acetyl H OH diphosphate acetyl acetyl H NH₂diphosphate acetyl acetyl H NH-cyclopropyl diphosphate acetyl acetyl HOH triphosphate acetyl acetyl H NH₂ triphosphate acetyl acetyl HNH-cyclopropyl triphosphate acetyl acetyl H OH

Alternatively, the following nucleosides of Formula VII are prepared,using the appropriate sugar and pyrimidine or purine bases.

(VII)

wherein: R¹ R² R³ R⁶ X Base H H H CH₃ O 2,4-O- Diacetyluracil H H H CH₃O Hypoxanthine H H H CH₃ O 2,4-O- Diacetylthymine H H H CH₃ O Thymine HH H CH₃ O Cytosine H H H CH₃ O 4-(N-mono- acetyl)cytosine H H H CH₃ O4-(N,N- diacetyl)cytosine H H H CH₃ O Uracil H H H CH₃ O 5-FluorouracilH H H CH₃ S 2,4-O- Diacetyluraci H H H CH₃ S Hypoxanthine H H H CH₃ S2,4-O- Diacetylthymine H H H CH₃ S Thymine H H H CH₃ S Cytosine H H HCH₃ S 4-(N-mono- acetyl)cytosine H H H CH₃ S 4-(N,N- diacetyl)cytosine HH H CH₃ S Uracil H H H CH₃ S 5-Fluorouracil monophosphate H H CH₃ O2,4-O- Diacetyluracil monophosphate H H CH₃ O Hypoxanthine monophosphateH H CH₃ O 2,4-O- Diacetylthym monophosphate H H CH₃ O Thyminemonophosphate H H CH₃ O Cytosine monophosphate H H CH₃ O 4-(N-mono-acetyl)cytosine monophosphate H H CH₃ O 4-(N,N- diacetyl)cytosinemonophosphate H H CH₃ O Uracil monophosphate H H CH₃ O 5-Fluorouracilmonophosphate H H CH₃ S 2,4-O- Diacetyluracil monophosphate H H CH₃ SHypoxanthine monophosphate H H CH₃ S 2,4-O- Diacetylthym monophosphate HH CH₃ S Thymine monophosphate H H CH₃ S Cytosine monophosphate H H CH₃ S4-(N-mono- acetyl)cytosine monophosphate H H CH₃ S 4-(N,N-diacetyl)cytosine monophosphate H H CH₃ S Uracil monophosphate H H CH₃ S5-Fluorouracil diphosphate H H CH₃ O 2,4-O- Diacetyluracil diphosphate HH CH₃ O Hypoxanthine diphosphate H H CH₃ O 2,4-O- Diacetylthyminediphosphate H H CH₃ O Thymine diphosphate H H CH₃ O Cytosine diphosphateH H CH₃ O 4-(N-mono- acetyl)cytosine diphosphate H H CH₃ O 4-(N,N-diacetyl)cytosine diphosphate H H CH₃ O Uracil diphosphate H H CH₃ O5-Fluorouracil diphosphate H H CH₃ S 2,4-O- Diacetyluracil diphosphate HH CH₃ S Hypoxanthine diphosphate H H CH₃ S 2,4-O- Diacetylthymdiphosphate H H CH₃ S Thymine diphosphate H H CH₃ S Cytosinetriphosphate H H CH₃ O 2,4-O- Diacetyluracil triphosphate H H CH₃ OHypoxanthine triphosphate H H CH₃ O 2,4-O- Diacetylthymine triphosphateH H CH₃ O Thymine triphosphate H H CH₃ O Cytosine triphosphate H H CH₃ O4-(N-mono- acetyl)cytosine triphosphate H H CH₃ O 4-(N,N-diacetyl)cytosine triphosphate H H CH₃ O Uracil triphosphate H H CH₃ O5-Fluorouracil triphosphate H H CH₃ S 2,4-O- Diacetyluracil triphosphateH H CH₃ S Hypoxanthine triphosphate H H CH₃ S 2,4-O- Diacetylthyminetriphosphate H H CH₃ S Thymine triphosphate H H CH₃ S Cytosinemonophosphate monophosphate monophosphate CF₃ O 2,4-O- Diacetyluracilmonophosphate monophosphate monophosphate CF₃ O Hypoxanthinemonophosphate monophosphate monophosphate CF₃ O 2,4-O- Diacetylthyminemonophosphate monophosphate monophosphate CF₃ O Thymine monophosphatemonophosphate monophosphate CF₃ O Cytosine monophosphate monophosphatemonophosphate CF₃ O 4-(N-mono- acetyl)cytosine monophosphatemonophosphate monophosphate CF₃ O 4-(N,N- diacetyl)cytosinemonophosphate monophosphate monophosphate CF₃ O Uracil monophosphatemonophosphate monophosphate CF₃ O 5-Fluorouracil monophosphatemonophosphate monophosphate CF₃ S 2,4-O- Diacetyluracil monophosphatemonophosphate monophosphate CF₃ S Hypoxanthine monophosphatemonophosphate monophosphate CF₃ S 2,4-O- Diacetylthymine monophosphatemonophosphate monophosphate CF₃ S Thymine monophosphate monophosphatemonophosphate CF₃ S Cytosine monophosphate monophosphate monophosphateCF₃ S 4-(N-mono- acetyl)cytosine monophosphate monophosphatemonophosphate CF₃ S 4-(N,N- diacetyl)cytosine monophosphatemonophosphate monophosphate CF₃ S Uracil monophosphate monophosphatemonophosphate CF₃ S 5-Fluorouracil acetyl acetyl acetyl CF₃ O 4-(N,N-diacetyl)cytosine acetyl acetyl acetyl CF₃ S 4-(N,N- diacetyl)cytosineacetyl acetyl acetyl 2-bromo- O 4-(N,N- vinyl diacetyl)cytosine acetylacetyl acetyl 2-bromo- S 4-(N,N- vinyl diacetyl)cytosine H H H CH₃ O2-(N,N-diacetyl)- guanine H H H CH₃ O 6-O-acetyl guanine H H H CH₃ O8-fluoroguanine H H H CH₃ O guanine H H H CH₃ O 6-(N,N-diacetyl)-adenine H H H CH₃ O 2-fluoroadenine H H H CH₃ O 8-fluoroadenine H H HCH₃ O 2,8-difluoro- adenine H H H CH₃ O adenine H H H CH₃ S2-(N,N-diacetyl)- guanine H H H CH₃ S 6-O-acetyl guanine H H H CH₃ S8-fluoroguanine H H H CH₃ S guanine H H H CH₃ S 6-(N,N-diacetyl)-adenine H H H CH₃ S 2-fluoroadenine H H H CH₃ S 8-fluoroadenine H H HCH₃ S 2,8-difluoro- adenine H H H CH₃ S adenine monophosphate H H CH₃ O2-(N,N-diacetyl)- guanine monophosphate H H CH₃ O 6-O-acetyl guaninemonophosphate H H CH₃ O 8-fluoroguanine monophosphate H H CH₃ O guaninemonophosphate H H CH₃ O 6-(N,N-diacetyl)- adenine monophosphate H H CH₃O 2-fluoroadenine monophosphate H H CH₃ O 8-fluoroadenine monophosphateH H CH₃ O 2,8-difluoro- adenine monophosphate H H CH₃ O adeninemonophosphate H H CH₃ S 2-(N,N-diacetyl)- guanine monophosphate H H CH₃S 6-O-acetyl guanine monophosphate H H CH₃ S 8-fluoroguaninemonophosphate H H CH₃ S guanine monophosphate H H CH₃ S6-(N,N-diacetyl)- adenine monophosphate H H CH₃ S 2-fluoroadeninemonophosphate H H CH₃ S 8-fluoroadenine monophosphate H H CH₃ S2,8-difluoro- adenine monophosphate H H CH₃ S adenine diphosphate H HCH₃ O 2-(N,N-diacetyl)- guanine diphosphate H H CH₃ O 6-O-acetyl guaninediphosphate H H CH₃ O 8-fluoroguanine diphosphate H H CH₃ O guaninediphosphate H H CH₃ O 6-(N,N-diacetyl)- adenine diphosphate H H CH₃ O2-fluoroadenine diphosphate H H CH₃ O 8-fluoroadenine diphosphate H HCH₃ O 2,8-difluoro- adenine diphosphate H H CH₃ O adenine diphosphate HH CH₃ S 2-(N,N-diacetyl)- guanine diphosphate H H CH₃ S 6-O-acetylguanine diphosphate H H CH₃ S 8-fluoroguanine diphosphate H H CH₃ Sguanine diphosphate H H CH₃ S 6-(N,N-diacetyl)- adenine diphosphate H HCH₃ S 2-fluoroadenine diphosphate H H CH₃ S 8-fluoroadenine diphosphateH H CH₃ S 2,8-difluoro- adenine diphosphate H H CH₃ S adeninetriphosphate H H CH₃ O 2-(N,N-diacetyl)- guanine triphosphate H H CH₃ O6-O-acetyl guanine triphosphate H H CH₃ O 8-fluoroguanine triphosphate HH CH₃ O guanine triphosphate H H CH₃ O 6-(N,N-diacetyl)- adeninetriphosphate H H CH₃ O 2-fluoroadenine triphosphate H H CH₃ O8-fluoroadenine triphosphate H H CH₃ O 2,8-difluoro- adeninetriphosphate H H CH₃ O 2-(N,N-diacetyl)- guanine triphosphate H H CH₃ S6-O-acetyl- guanine triphosphate H H CH₃ S 8-fluoroguanine triphosphateH H CH₃ S guanine triphosphate H H CH₃ S 6-(N,N-diacetyl)- adeninetriphosphate H H CH₃ S 2-fluoroadenine triphosphate H H CH₃ S8-fluoroadenine triphosphate H H CH₃ S 2,8-difluoro- adeninetriphosphate H H CH₃ S adenine monophosphate monophosphate monophosphateCF₃ O 2-(N,N-diacetyl)- guanine monophosphate monophosphatemonophosphate CF₃ O 6-O-acetyl guanine monophosphate monophosphatemonophosphate CF₃ O 8-fluoroguanine monophosphate monophosphatemonophosphate CF₃ O guanine monophosphate monophosphate monophosphateCF₃ O 6-(N,N-diacetyl)- adenine monophosphate monophosphatemonophosphate CF₃ O 2-fluoroadenine monophosphate monophosphatemonophosphate CF₃ O 8-fluoroadenine monophosphate monophosphatemonophosphate CF₃ O 2,8-difluoro- adenine monophosphate monophosphatemonophosphate CF₃ O adenine monophosphate monophosphate monophosphateCF₃ S 2-(N,N-diacetyl)- guanine monophosphate monophosphatemonophosphate CF₃ S 6-O-acetyl guanine monophosphate monophosphatemonophosphate CF₃ S 8-fluoroguanine monophosphate monophosphatemonophosphate CF₃ S guanine monophosphate monophosphate monophosphateCF₃ S 6-(N,N-diacetyl)- adenine monophosphate monophosphatemonophosphate CF₃ S 2-fluoroadenine monophosphate monophosphatemonophosphate CF₃ S 8-fluoroadenine monophosphate monophosphatemonophosphate CF₃ S 2,8-difluoro- adenine monophosphate monophosphatemonophosphate CF₃ S adenine acetyl acetyl acetyl CF₃ O guanine acetylacetyl acetyl CF₃ S guanine acetyl acetyl acetyl 2-bromo- O guaninevinyl acetyl acetyl acetyl 2-bromo- S guanine vinyl

Alternatively, the following nucleosides of Formula VIII are prepared,using the appropriate sugar and pyrimidine or purine bases.

(VIII)

wherein R¹ R² R⁶ X Base H H CH₃ O 2,4-O-Diacetyluracil H H CH₃ OHypoxanthine H H CH₃ O 2,4-O-Diacetylthymine H H CH₃ O Thymine H H CH₃ OCytosine H H CH₃ O 4-(N-mono-acetyl)cytosine H H CH₃ O4-(N,N-diacetyl)cytosine H H CH₃ O Uracil H H CH₃ O 5-Fluorouracil H HCH₃ S 2,4-O-Diacetyluracil H H CH₃ S Hypoxanthine H H CH₃ S2,4-O-Diacetylthymine H H CH₃ S Thymine H H CH₃ S Cytosine H H CH₃ S4-(N-mono-acetyl)cytosine H H CH₃ S 4-(N,N-diacetyl)cytosine H H CH₃ SUracil H H CH₃ S 5-Fluorouracil monophosphate H CH₃ O2,4-O-Diacetyluracil monophosphate H CH₃ O Hypoxanthine monophosphate HCH₃ O 2,4-O-Diacetylthymine monophosphate H CH₃ O Thymine monophosphateH CH₃ O Cytosine monophosphate H CH₃ O 4-(N-mono-acetyl)cytosinemonophosphate H CH₃ O 4-(N,N-diacetyl)cytosine monophosphate H CH₃ OUracil monophosphate H CH₃ O 5-Fluorouracil monophosphate H CH₃ S2,4-O-Diacetyluracil monophosphate H CH₃ S Hypoxanthine monophosphate HCH₃ S 2,4-O-Diacetylthymine monophosphate H CH₃ S Thymine monophosphateH CH₃ S Cytosine monophosphate H CH₃ S 4-(N-mono-acetyl)cytosinemonophosphate H CH₃ S 4-(N,N-diacetyl)cytosine monophosphate H CH₃ SUracil monophosphate H CH₃ S 5-Fluorouracil diphosphate H CH₃ O2,4-O-Diacetyluracil diphosphate H CH₃ O Hypoxanthine diphosphate H CH₃O 2,4-O-Diacetylthymine diphosphate H CH₃ O Thymine diphosphate H CH₃ OCytosine diphosphate H CH₃ O 4-(N-mono-acetyl)cytosine diphosphate H CH₃O 4-(N,N-diacetyl)cytosine diphosphate H CH₃ O Uracil diphosphate H CH₃O 5-Fluorouracil diphosphate H CH₃ S 2,4-O-Diacetyluracil diphosphate HCH₃ S Hypoxanthine diphosphate H CH₃ S 2,4-O-Diacetylthymine diphosphateH CH₃ S Thymine diphosphate H CH₃ S Cytosine diphosphate H CH₃ S4-(N-mono-acetyl)cytosine diphosphate H CH₃ S 4-(N,N-diacetyl)cytosinediphosphate H CH₃ S Uracil diphosphate H CH₃ S 5-Fluorouraciltriphosphate H CH₃ O 2,4-O-Diacetyluracil triphosphate H CH₃ OHypoxanthine triphosphate H CH₃ O 2,4-O-diacethylthymine triphosphate HCH₃ O Thymine triphosphate H CH₃ O Cytosine triphosphate H CH₃ O4-(N-mono-acetyl)cytosine triphosphate H CH₃ O 4-(N,N-diacetyl)cytosinetriphosphate H CH₃ O Uracil triphosphate H CH₃ O 5-Fluorouraciltriphosphate H CH₃ S 2,4-O-Diacetyluracil triphosphate H CH₃ SHypoxanthine triphosphate H CH₃ S 2,4-O-Diacetylthymine triphosphate HCH₃ S Thymine triphosphate H CH₃ S Cytsine triphosphate H CH₃ S4-(N-mono-acetyl)cytosine triphosphate H CH₃ S 4-(N,N-diacetyl)cytosinetriphosphate H CH₃ S Uracil triphosphate H CH₃ S 5-Fluorouracilmonophosphate monophosphate CF₃ O 2,4-O-Diacetyluracil monophosphatemonophosphate CF₃ O Hypoxanthine monophosphate monophosphate CF₃ O2,4-O-Diacetylthymine monophosphate monophosphate CF₃ O Thyminemonophosphate monophosphate CF₃ O Cytosine monophosphate monophosphateCF₃ O 4-(N-mono-acetyl)cytosine monophosphate monophosphate CF₃ O4-(N,N-diacetyl)cytosine monophosphate monophosphate CF₃ O Uracilmonophosphate monophosphate CF₃ O 5-Fluorouracil monophosphatemonophosphate CF₃ S 2,4-O-Diacetyluracil monophosphate monophosphate CF₃S Hypoxanthine monophosphate monophosphate CF₃ S 2,4-O-Diacetylthyminemonophosphate monophosphate CF₃ S Thymine monophosphate monophosphateCF₃ S Cytosine monophosphate monophosphate CF₃ S4-(N-mono-acetyl)cytosine monophosphate monophosphate CF₃ S4-(N,N-diacetyl)cytosine monophosphate monophosphate CF₃ S Uracilmonophosphate monophosphate CF₃ S 5-Fluorouracil acetyl acetyl CF₃ O4-(N,N-diacetyl)cytosine acetyl acetyl CF₃ S 4-(N,N-diacetyl)cytosineacetyl acetyl 2-bromo- O 4-(N,N-diacetyl)cytosine vinyl acetyl acetyl2-bromo- S 4-(N,N-diacetyl)cytosine vinyl H H CH₃ O2-(N,N-diacetyl)-guanine H H CH₃ O 6-O-acetyl guanine H H CH₃ O8-fluoroguanine H H CH₃ O guanine H H CH₃ O 6-(N,N-diacetyl)-adenine H HCH₃ O 2-fluoroadenine H H CH₃ O 8-fluoroadenine H H CH₃ O2,8-difluoro-adenine H H CH₃ O adenine H H CH₃ S2-(N,N-diacetyl)-guanine H H CH₃ S 6-O-acetyl guanine H H CH₃ S8-fluoroguanine H H CH₃ S guanine H H CH₃ S 6-(N,N-diacetyl)-adenine H HCH₃ S 2-fluoroadenine H H CH₃ S 8-fluoroadenine H H CH₃ S2,8-difluoro-adenine H H CH₃ S adenine monophosphate H CH₃ O2-(N,N-diacetyl)-guanine monophosphate H CH₃ O 6-O-acetyl guaninemonophosphate H CH₃ O 8-fluoroguanine monophosphate H CH₃ O guaninemonophosphate H CH₃ O 6-(N,N-diacetyl)-adenine monophosphate H CH₃ O2-fluoroadenine monophosphate H CH₃ O 8-fluoroadenine monophosphate HCH₃ O 2,8-difluoro-adenine monophosphate H CH₃ O adenine monophosphate HCH₃ S 2-(N,N-diacetyl)-guanine monophosphate H CH₃ S 6-O-acetyl guaninemonophosphate H CH₃ S 8-fluoroguanine monophosphate H CH₃ S guaninemonophosphate H CH₃ S 6-(N,N-diacetyl)-adenine monophosphate H CH₃ S2-fluoroadenine monophosphate H CH₃ S 8-fluoroadenine monophosphate HCH₃ S 2,8-difluoro-adenine monophosphate H CH₃ S adenine diphosphate HCH₃ O 2-(N,N-diacetyl)-guanine diphosphate H CH₃ O 6-O-acetyl guaninediphosphate H CH₃ O 8-fluoroguanine diphosphate H CH₃ O guaninediphosphate H CH₃ O 6-(N,N-diacetyl)-adenine diphosphate H CH₃ O2-fluoroadenine diphosphate H CH₃ O 8-fluoroadenine diphosphate H CH₃ O2,8-difluoro-adenine diphosphate H CH₃ O adenine diphosphate H CH₃ S2-(N,N-diacetyl)-guanine diphosphate H CH₃ S 6-O-acetyl guaninediphosphate H CH₃ S 8-fluoroguanine diphosphate H CH₃ S guaninediphosphate H CH₃ S 6-(N,N-diacety)-adenine diphosphate H CH₃ S2-fluoroadenine diphosphate H CH₃ S 8-fluoroadenine diphosphate H CH₃ S2,8-difluoro-adenine diphosphate H CH₃ S adenine triphosphate H CH₃ O2-(N,N-diacetyl)-guanine triphosphate H CH₃ O 6-O-acetyl guaninetriphosphate H CH₃ O 8-fluoroguanine triphosphate H CH₃ O guaninetriphosphate H CH₃ O 6-(N,N-diacetyl)-adenine triphosphate H CH₃ O2-fluoroadenine triphosphate H CH₃ O 8-fluoroadenine triphosphate H CH₃O 2,8-difluoro-adenine triphosphate H CH₃ O adenine triphosphate H CH₃ S2-(N,N-diacetyl)-guanine triphosphate H CH₃ S 6-O-acetyl guaninetriphosphate H CH₃ S 8-fluoroguanine triphosphate H CH₃ S guaninetriphosphate H CH₃ S 6-(N,N-diacetyl)-adenine triphosphate H CH₃ S2-fluoroadenine triphosphate H CH₃ S 8-fluoroadenine triphosphate H CH₃S 2,8-difluoro-adenine triphosphate H CH₃ S adenine monophosphatemonophosphate CF₃ O 2-(N,N-diacetyl)-guanine monophosphate monophosphateCF₃ O 6-O-acetyl guanine monophosphate monophosphate CF₃ O8-fluoroguanine monophosphate monophosphate CF₃ O guanine monophosphatemonophosphate CF₃ O 6-(N,N-diacetyl)-adenine monophosphate monophosphateCF₃ O 2-fluoroadenine monophosphate monophosphate CF₃ O 8-fluoroadeninemonophosphate monophosphate CF₃ O 2,8-difluoro-adenine monophosphatemonophosphate CF₃ O adenine monophosphate monophosphate CF₃ S2-(N,N-diacetyl)-guanine monophosphate monophosphate CF₃ S 6-O-acetylguanine monophosphate monophosphate CF₃ S 8-fluoroguanine monophosphatemonophosphate CF₃ S guanine monophosphate monophosphate CF₃ S6-(N,N-diacetyl)-adenine monophosphate monophosphate CF₃ S2-fluoroadenine monophosphate monophosphate CF₃ S 8-fluoroadeninemonophosphate monophosphate CF₃ S 2,8-difluoro-adenine monophosphatemonophosphate CF₃ S adenine acetyl acetyl CF₃ O guanine acetyl acetylCF₃ S guanine acetyl acetyl 2-bromo- O guanine vinyl acetyl acetyl2-bromo- S guanine vinyl

Alternatively, the following nucleosides of Formula IX are prepared,using the appropriate sugar and pyrimidine or purine bases.

(IX)

wherein: R¹ R⁶ X Base H CH₃ O 2,4-O-Diacetyluracil H CH₃ O HypoxanthineH CH₃ O 2,4-O-Diacetylthymine H CH₃ O Thymine H CH₃ O Cytosine H CH₃ O4-(N-mono-acetyl)cytosine H CH₃ O 4-(N,N-diacetyl)cytosine H CH₃ OUracil H CH₃ O 5-Fluorouracil H CH₃ S 2,4-O-Diacetyluracil H CH₃ SHypoxanthine H CH₃ S 2,4-O-Diacetylthymine H CH₃ S Thymine H CH₃ SCytosine H CH₃ S 4-(N-mono-acetyl)cytosine H CH₃ S4-(N,N-diacetyl)cytosine H CH₃ S Uracil H CH₃ S 5-Fluorouracilmonophosphate CH₃ O 2,4-O-Diacetyluracil monophosphate CH₃ OHypoxanthine monophosphate CH₃ O 2,4-O-Diacetylthymine monophosphate CH₃O Thymine monophosphate CH₃ O Cytosine monophosphate CH₃ O4-(N-mono-acetyl)cytosine monophosphate CH₃ O 4-(N,N-diacetyl)cytosinemonophosphate CH₃ O Uracil monophosphate CH₃ O 5-Fluorouracilmonophosphate CH₃ S 2,4-O-Diacetyluracil monophosphate CH₃ SHypoxanthine monophosphate CH₃ S 2,4-O-Diacetylthymine monophosphate CH₃S Thymine monophosphate CH₃ S Cytosine monophosphate CH₃ S4-(N-mono-acetyl)cytosine monophosphate CH₃ S 4-(N,N-diacetyl)cytosmonophosphate CH₃ S Uracil monophosphate CH₃ S 5-Fluorouracildiphosphate CH₃ O 2,4-O-Diacetyluracil diphosphate CH₃ O Hypoxanthinediphosphate CH₃ O 2,4-O-Diacetylthymine diphosphate CH₃ O Thyminediphosphate CH₃ O Cytosine diphosphate CH₃ O 4-(N-mono-acetyl)cytosinediphosphate CH₃ O 4-(N,N-diacetyl)cytosine diphosphate CH₃ O Uracildiphosphate CH₃ O 5-Fluorouracil diphosphate CH₃ S 2,4-O-Diacetyluracildiphosphate CH₃ S Hypoxanthine diphosphate CH₃ S 2,4-O-Diacetylthyminediphosphate CH₃ S Thymine diphosphate CH₃ S Cytosine triphosphate CH₃ O2,4-O-Diacetyluracil triphosphate CH₃ O Hypoxanthine triphosphate CH₃ O2,4-O-Diacetylthymine triphosphate CH₃ O Thymine triphosphate CH₃ OCytosine triphosphate CH₃ O 4-(N-mono-acetyl)cytosine triphosphate CH₃ O4-(N,N-diacetyl)cytosine triphosphate CH₃ O Uracil triphosphate CH₃ O5-Fluorouracil triphosphate CH₃ S 2,4-O-Diacetyluracil triphosphate CH₃S Hypoxanthine triphospahate CH₃ S 2,4-O-Diacetylthymine triphospahateCH₃ S Thymine triphospahate CH₃ S Cytosine monophosphate CF₃ O2,4-O-Diacetyluracil monophosphate CF₃ O Hypoxanthine monophosphate CF₃O 2,4-O-Diacetylthymine monophosphate CF₃ O Thymine monophosphate CF₃ OCytosine monophosphate CF₃ O 4-(N-mono-acetyl)cytosine monophosphate CF₃O 4-(N,N-diacetyl)cytos monophosphate CF₃ O Uracil monophosphate CF₃ O5-Fluorouracil monophosphate CF₃ S 2,4-O-Diacetyluracil monophosphateCF₃ S Hypoxanthine monophosphate CF₃ S 2,4-O-Diacetylthyminemonophosphate CF₃ S Thymine monophosphate CF₃ S Cytosine monophosphateCF₃ S 4-(N-mono-acetyl)cytosine monophosphate CF₃ S4-(N,N-diacetyl)cytosine monophosphate CF₃ S Uracil monophosphate CF₃ S5-Fluorouracil acetyl CF₃ O 4-(N,N-diacetyl)cytosine acetyl CF₃ S4-(N,N-diacetyl)cytosine acetyl 2-bromo-vinyl O 4-(N,N-diacetyl)cytosineacetyl 2-bromo-vinyl S 4-(N,N-diacetyl)cytosine

Alternatively, the following nucleosides of Formula XVI are prepared,using the appropriate sugar and pyrimidine or purine bases.

(XVI)

wherein: R¹ R⁶ R⁷ R⁸ X Base R¹⁰ R⁹ H CH₃ H H O 2,4-O-Diacetyluracil OHMe H CH₃ H H O Hypoxanthine OH Me H CH₃ H H O 2,4-O-Diacetylthymine OHMe H CH₃ H H O Thymine OH Me H CH₃ H H O Cytosine OH Me H CH₃ H H O4-(N-mono-acetyl)cytosine OH Me H CH₃ H H O 4-(N,N-diacetyl)cytosine OHMe H CH₃ H H O Uracil OH Me H CH₃ H H O 5-Fluorouracil OH Me H CH₃ H H S2,4-O-Diacetyluracil OH Me H CH₃ H H S Hypoxanthine OH Me H CH₃ H H S2,4-O-Diacetylthymine OH Me H CH₃ H H S Thymine OH Me H CH₃ H H SCytosine OH Me H CH₃ H H S 4-(N-mono-acetyl)cytosine OH Me H CH₃ H H S4-(N,N-diacetyl)cytosine OH Me H CH₃ H H S Uracil OH Me H CH₃ H H S5-Fluorouracil OH Me monophosphate CH₃ H H O 2,4-O-Diacetyluracil OH Memonophosphate CH₃ H H O Hypoxanthine OH Me monophosphate CH₃ H H O2,4-O-Diacetylthymine OH Me monophosphate CH₃ H H O Thymine OH Memonophosphate CH₃ H H O Cytosine OH Me monophosphate CH₃ H H O4-(N-mono-acetyl)cytosine OH Me monophosphate CH₃ H H O4-(N,N-diacetyl)cytosine OH Me monophosphate CH₃ H H O Uracil OH Memonophosphate CH₃ H H O 5-Fluorouracil OH Me monophosphate CH₃ H H S2,4-O-Diacetyluracil OH Me monophosphate CH₃ H H S Hypoxanthine OH Memonophosphate CH₃ H H S 2,4-O-Diacetylthymine OH Me monophosphate CH₃ HH S Thymine OH Me monophosphate CH₃ H H S Cytosine OH Me monophosphateCH₃ H H S 4-(N-mono-acetyl)cytosine OH Me monophosphate CH₃ H H S4-(N,N-diacetyl)cytosine OH Me monophosphate CH₃ H H S Uracil OH Memonophosphate CH₃ H H S 5-Fluorouracil OH Me diphosphate CH₃ H H O2,4-O-Diacetyluracil OH Me diphosphate CH₃ H H O Hypoxanthine OH Mediphosphate CH₃ H H O 2,4-O-Diacetylthymine OH Me diphosphate CH₃ H H OThymine OH Me diphosphate CH₃ H H O Cytosine OH Me diphosphate CH₃ H H O4-(N-mono-acetyl)cytosine OH Me diphosphate CH₃ H H O4-(N,N-diacetyl)cytosine OH Me diphosphate CH₃ H, H O Uracil OH Mediphosphate CH₃ H H O 5-Fluorouracil OH Me diphosphate CH₃ H H S2,4-O-Diacetyluracil OH Me diphosphate CH₃ H H S Hypoxanthine OH Mediphosphate CH₃ H H S 2,4-O-Diacetylthymine OH Me diphosphate CH₃ H H SThymine OH Me diphosphate CH₃ H H S Cytosine OH Me triphosphate CH₃ H HO 2,4-O-Diacetyluracil OH Me triphosphate CH₃ H H O Hypoxanthine OH Metriphosphate CH₃ H H O 2,4-O-Diacetylthymine OH Me triphosphate CH₃ H HO Thymine OH Me triphosphate CH₃ H H O Cytosine OH Me triphosphate CH₃ HH O 4-(N-mono-acetyl)cytosine OH Me triphosphate CH₃ H H O4-(N,N-diacetyl)cytosine OH Me triphosphate CH₃ H H O Uracil OH Metriphosphate CH₃ H H O 5-Fluorouracil OH Me triphosphate CH₃ H H S2,4-O-Diacetyluracil OH Me triphosphate CH₃ H H S Hypoxanthine OH Metriphosphate CH₃ H H S 2,4-O-Diacetylthymine OH Me triphosphate CH₃ H HS Thymine OH Me triphosphate CH₃ H H S Cytosine OH Me monophosphate CF₃H H O 2,4-O-Diacetyluracil OH Me monophosphate CF₃ H H O Hypoxanthine OHMe monophosphate CF₃ H H O 2,4-O-Diacetylthymine OH Me monophosphate CF₃H H O Thymine OH Me monophosphate CF₃ H H O Cytosine OH Me monophosphateCF₃ H H O 4-(N-mono-acetyl)cytosine OH Me monophosphate CF₃ H H O4-(N,N-diacetyl)cytosine OH Me monophosphate CF₃ H H O Uracil OH Memonophosphate CF₃ H H O 5-Fluorouracil OH Me monophosphate CF₃ H H S2,4-O-Diacetyluracil OH Me monophosphate CF₃ H H S Hypoxanthine OH Memonophosphate CF₃ H H S 2,4-O-Diacetylthymine OH Me monophosphate CF₃ HH S Thymine OH Me monophosphate CF₃ H H S Cytosine OH Me monophosphateCF₃ H H S 4-(N-mono-acetyl)cytosine OH Me monophosphate CF₃ H H S4-(N,N-diacetyl)cytosine OH Me monophosphate CF₃ H H S Uracil OH Memonophosphate CF₃ H H S 5-Fluorouracil OH Me acetyl CH₃ H H O4-(N,N-diacetyl)cytosine H Br acetyl CH₃ H H S 4-(N,N-diacetyl)cytosineH Br acetyl CH₃ OH H O 4-(N,N-diacetyl)cytosine H Br acetyl CH₃ OH H S4-(N,N-diacetyl)cytosine H Br

Example 2 Preparation of 2′-C-methylriboadenine

The title compound was prepared according to a published procedure (R.E. Harry-O'kuru, J. M. Smith, and M. S. Wolfe, “A short, flexible routetoward 2′-C-branched ribonucleosides”, J. Org. Chem. 1997, 62 1754-1759)(Scheme 8).

In a similar manner, but using the appropriate sugar and pyrimidine orpurine bases, the following nucleosides of Formula H are prepared.

(II)

wherein: R¹ R² R³ X¹ X² Y H H H H H H H H H H H NH₂ H H H H HNH-cyclopropyl H H H H H NH-methyl H H H H H NH-ethyl H H H H HNH-acetyl H H H H H OH H H H H H OMe H H H H H OEt H H H H HO-cyclopropyl H H H H H O-acetyl H H H H H SH H H H H H SMe H H H H HSEt H H H H H S-cyclopropyl H H H H H F H H H H H Cl H H H H H Br H H HH H I monophosphate H H H H NH₂ monophosphate H H H H NH-acetyl

nophosphate H H H H NH-cyclopropyl monophosphate H H H H NH-methylmonophosphate H H H H NH-ethyl

e H H H H OH

ate H H H H O-acetyl monopho

te H H H H OMe

sphate H H H H OEt

e H H H H O-cyclopropyl monophosphate H H H H SH monophosphate H H H HSMe monophosphate H H H H SEt monophosphate H H H H S-cyclopropylmonophosphate H H H H F monophosphate H H H H Cl monophosphate H H H HBr monophosphate H H H H I diphosphate H H H H NH₂ diphosphate H H H HNH-acetyl diphosphate H H H H NH-cyclopropyl diphosphate H H H HNH-methyl diphosphate H H H H NH-ethyl diphosphate H H H H OHdiphosphate H H H H O-acetyl diphosphate H H H H OMe diphosphate H H H HOEt diphosphate H H H H O-cyclopropyl diphosphate H H H H SH diphosphateH H H H SMe diphosphate H H H H SEt diphosphate H H H H S-cyclopropyldiphosphate H H H H F diphosphate H H H H Cl diphosphate H H H H Brdiphosphate H H H H I triphosphate H H H H NH₂ triphosphate H H H HNH-acetyl triphosphate H H H H NH-cyclopropyl triphosphate H H H HNH-methyl triphosphate H H H H NH-ethyl triphosphate H H H H OHtriphosphate H H H H OMe triphosphate H H H H OEt triphosphate H H H HO-cyclopropyl triphosphate H H H H O-acetyl triphosphate H H H H SHtriphosphate H H H H SMe triphosphate H H H H SEt triphosphate H H H HS-cyclopropyl triphosphate H H H H F triphosphate H H H H Cltriphosphate H H H H Br triphosphate H H H H I monophosphatemonophosphate monophosphate H H NH₂ monophosphate monophosphatemonophosphate H H NH-cyclopropyl monophosphate monophosphatemonophosphate H H OH monophosphate monophosphate monophosphate H H Fmonophosphate monophosphate monophosphate H H Cl diphosphate diphosphatediphosphate H H NH₂ diphosphate diphosphate diphosphate H HNH-cyclopropyl diphosphate diphosphate diphosphate H H OH diphosphatediphosphate diphosphate H H F diphosphate diphosphate diphosphate H H Cltriphosphate triphosphate triphosphate H H NH₂ triphosphate triphosphatetriphosphate H H NH-cyclopropyl triphosphate triphosphate triphosphate HH OH triphosphate triphosphate triphosphate H H F triphosphatetriphosphate triphosphate H H Cl H H H F H NH₂ H H H F H NH-cyclopropylH H H F H OH H H H F H F H H H F H Cl H H H Cl H NH₂ H H H Cl HNH-cyclopropyl H H H Cl H OH H H H Cl H F H H H Cl H Cl H H H Br H NH₂ HH H Br H NH-cyclopropyl H H H Br H OH H H H Br H F H H H Br H Cl H H HNH₂ H NH₂ H H H NH₂ H NH-cyclopropyl H H H NH₂ H OH H H H NH₂ H F H H HNH₂ H Cl H H H SH H NH₂ H H H SH H NH-cyclopropyl H H H SH H OH H H H SHH F H H H SH H Cl acetyl H H H H NH₂ acetyl H H H H NH-cyclopropylacetyl H H H H OH acetyl H H H H F acetyl H H H H Cl acetyl H H F H NH₂acetyl H H F H NH-cyclopropyl acetyl H H F H OH acetyl H H F H F acetylH H F H Cl H acetyl acetyl H H NH₂ H acetyl acetyl H H NH-cyclopropyl Hacetyl acetyl H H OH H acetyl acetyl H H F H acetyl acetyl H H Cl acetylacetyl acetyl H H NH₂ acetyl acetyl acetyl H H NH-cyclopropyl acetylacetyl acetyl H H OH acetyl acetyl acetyl H H F acetyl acetyl acetyl H HCl monophosphate acetyl acetyl H H NH₂ monophosphate acetyl acetyl H HNH-cyclopropyl monophosphate acetyl acetyl H H OH monophosphate acetylacetyl H H F monophosphate acetyl acetyl H H Cl diphosphate acetylacetyl H H NH₂ diphosphate acetyl acetyl H H NH-cyclopropyl diphosphateacetyl acetyl H H OH diphosphate acetyl acetyl H H F diphosphate acetylacetyl H H Cl triphosphate acetyl acetyl H H NH₂ triphosphate acetylacetyl H H NH-cyclopropyl triphosphate acetyl acetyl H H OH triphosphateacetyl acetyl H H F triphosphate acetyl acetyl H H Cl H H H H NH₂ H H HH H NH₂ NH₂ H H H H NH₂ NH-cyclopropyl H H H H NH₂ NH-methyl H H H H NH₂NH-ethyl H H H H NH₂ NH-acetyl H H H H NH₂ OH H H H H NH₂ OMe H H H HNH₂ OEt H H H H NH₂ O-cyclopropyl H H H H NH₂ O-acetyl H H H H NH₂ SH HH H H NH₂ SMe H H H H NH₂ SEt H H H H NH₂ S-cyclopropyl H H H H NH₂ F HH H H NH₂ Cl H H H H NH₂ Br H H H H NH₂ I monophosphate H H H NH₂ NH₂monophosphate H H H NH₂ NH-acetyl monophosphate H H H NH₂ NH-cyclopropylmonophosphate H H H NH₂ NH-methyl monophosphate H H H NH₂ NH-ethylmonophosphate H H H NH₂ OH monophosphate H H H NH₂ O-acetylmonophosphate H H H NH₂ OMe monophosphate H H H NH₂ OEt monophosphate HH H NH₂ O-cyclopropyl monophosphate H H H NH₂ SH monophosphate H H H NH₂SMe monophosphate H H H NH₂ SEt monophosphate H H H NH₂ S-cyclopropylmonophosphate H H H NH₂ F monophosphate H H H NH₂ Cl monophosphate H H HNH₂ Br monophosphate H H H NH₂ I diphosphate H H H NH₂ NH₂ diphosphate HH H NH₂ NH-acetyl diphosphate H H H NH₂ NH-cyclopropyl diphosphate H H HNH₂ NH-methyl diphosphate H H H NH₂ NH-ethyl diphosphate H H H NH₂ OHdiphosphate H H H NH₂ O-acetyl diphosphate H H H NH₂ OMe diphosphate H HH NH₂ OEt diphosphate H H H NH₂ O-cyclopropyl diphosphate H H H NH₂ SHdiphosphate H H H NH₂ SMe diphosphate H H H NH₂ SEt diphosphate H H HNH₂ S-cyclopropyl diphosphate H H H NH₂ F diphosphate H H H NH₂ Cldiphosphate H H H NH₂ Br diphosphate H H H NH₂ I triphosphate H H H NH₂NH₂ triphosphate H H H NH₂ NH-acetyl triphosphate H H H NH₂NH-cyclopropyl triphosphate H H H NH₂ NH-methyl triphosphate H H H NH₂NH-ethyl triphosphate H H H NH₂ OH triphosphate H H H NH₂ OMetriphosphate H H H NH₂ OEt triphosphate H H H NH₂ O-cyclopropyltriphosphate H H H NH₂ O-acetyl triphosphate H H H NH₂ SH triphosphate HH H NH₂ SMe triphosphate H H H NH₂ SEt triphosphate H H H NH₂S-cyclopropyl triphosphate H H H NH₂ F triphosphate H H H NH₂ Cltriphosphate H H H NH₂ Br triphosphate H H H NH₂ I monophosphatemonophosphate monophosphate H NH₂ NH₂ monophosphate monophosphatemonophosphate H NH₂ NH-cyclopropyl monophosphate monophosphatemonophosphate H NH₂ OH monophosphate monophosphate monophosphate H NH₂ Fmonophosphate monophosphate monophosphate H NH₂ Cl diphosphatediphosphate diphosphate H NH₂ NH₂ diphosphate diphosphate diphosphate HNH₂ NH-cyclopropyl diphosphate diphosphate diphosphate H NH₂ OHdiphosphate diphosphate diphosphate H NH₂ F diphosphate diphosphatediphosphate H NH₂ Cl triphosphate triphosphate triphosphate H NH₂ NH₂triphosphate triphosphate triphosphate H NH₂ NH-cyclopropyl triphosphatetriphosphate triphosphate H NH₂ OH triphosphate triphosphatetriphosphate H NH₂ F triphosphate triphosphate triphosphate H NH₂ Cl H HH F NH₂ NH₂ H H H F NH₂ NH-cyclopropyl H H H F NH₂ OH H H H F NH₂ F H HH F NH₂ Cl H H H Cl NH₂ NH₂ H H H Cl NH₂ NH-cyclopropyl H H H Cl NH₂ OHH H H Cl NH₂ F H H H Cl NH₂ Cl H H H Br NH₂ NH₂ H H H Br NH₂NH-cyclopropyl H H H Br NH₂ OH H H H Br NH₂ F H H H Br NH₂ Cl H H H NH₂NH₂ NH₂ H H H NH₂ NH₂ NH-cyclopropyl H H H NH₂ NH₂ OH H H H NH₂ NH₂ F HH H NH₂ NH₂ Cl H H H SH NH₂ NH₂ H H H SH NH₂ NH-cyclopropyl H H H SH NH₂OH H H H SH NH₂ F H H H SH NH₂ Cl acetyl H H H NH₂ NH₂ acetyl H H H NH₂NH-cyclopropyl acetyl H H H NH₂ OH acetyl H H H NH₂ F acetyl H H H NH₂Cl acetyl H H F NH₂ NH₂ acetyl H H F NH₂ NH-cyclopropyl acetyl H H F NH₂OH acetyl H H F NH₂ F acetyl H H F NH₂ Cl H acetyl acetyl H NH₂ NH₂ Hacetyl acetyl H NH₂ NH-cyclopropyl H acetyl acetyl H NH₂ OH H acetylacetyl H NH₂ F H acetyl acetyl H NH₂ Cl acetyl acetyl acetyl H NH₂ NH₂acetyl acetyl acetyl H NH₂ NH-cyclopropyl acetyl acetyl acetyl H NH₂ OHacetyl acetyl acetyl H NH₂ F acetyl acetyl acetyl H NH₂ Cl monophosphateacetyl acetyl H NH₂ NH₂ monophosphate acetyl acetyl H NH₂ NH-cyclopropylmonophosphate acetyl acetyl H NH₂ OH monophosphate acetyl acetyl H NH₂ Fmonophosphate acetyl acetyl H NH₂ Cl diphosphate acetyl acetyl H NH₂ NH₂diphosphate acetyl acetyl H NH₂ NH-cyclopropyl diphosphate acetyl acetylH NH₂ OH diphosphate acetyl acetyl H NH₂ F diphosphate acetyl acetyl HNH₂ Cl triphosphate acetyl acetyl H NH₂ NH₂ triphosphate acetyl acetyl HNH₂ NH-cyclopropyl triphosphate acetyl acetyl H NH₂ OH triphosphateacetyl acetyl H NH₂ F triphosphate acetyl acetyl H NH₂ Cl H H H H Cl H HH H H Cl H H H H H Cl NH₂ H H H H Cl NH-cyclopropyl H H H H Cl NH-methylH H H H Cl NH-ethyl H H H H Cl NH-acetyl H H H H Cl OH H H H H Cl OMe HH H H Cl OEt H H H H Cl O-cyclopropyl H H H H Cl O-acetyl H H H H Cl SHH H H H Cl SMe H H H H Cl SEt H H H H Cl S-cyclopropyl monophosphate H HH Cl NH₂ monophosphate H H H Cl NH-acetyl monophosphate H H H ClNH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H ClNH-ethyl monophosphate H H H Cl OH monophosphate H H H Cl O-acetylmonophosphate H H H Cl OMe monophosphate H H H Cl OEt monophosphate H HH Cl O-cyclopropyl monophosphate H H H Cl SH monophosphate H H H Cl SMemonophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyldiphosphate H H H Cl NH₂ diphosphate H H H Cl NH-acetyl diphosphate H HH Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H ClNH-ethyl diphosphate H H H Cl OH diphosphate H H H Cl O-acetyldiphosphate H H H Cl OMe diphosphate H H H Cl OEt diphosphate H H H ClO-cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMediphosphate H H H Cl SEt diphosphate H H H Cl S-cyclopropyl triphosphateH H H Cl NH₂ triphosphate H H H Cl NH-acetyl triphosphate H H H ClNH-cyclopropyl triphosphate H H H Cl NH-methyl triphosphate H H H ClNH-ethyl triphosphate H H H Cl OH triphosphate H H H Cl OMe triphosphateH H H Cl OEt triphosphate H H H Cl O-cyclopropyl triphosphate H H H ClO-acetyl triphosphate H H H Cl SH triphosphate H H H Cl SMe triphosphateH H H Cl SEt triphosphate H H H Cl S-cyclopropyl monophosphatemonophosphate monophosphate H Cl NH₂ monophosphate monophosphatemonophosphate H Cl N-cyclopropyl monophosphate monophosphatemonophosphate H Cl OH diphosphate diphosphate diphosphate H Cl NH₂diphosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphatediphosphate diphosphate H Cl OH triphosphate triphosphate triphosphate HCl NH₂ triphosphate triphosphate triphosphate H Cl NH-cyclopropyltriphosphate triphosphate triphosphate H Cl OH H H H F Cl NH₂ H H H F ClNH-cyclopropyl H H H F Cl OH H H H Cl Cl NH₂ H H H Cl Cl NH-cyclopropylH H H Cl Cl OH H H H Br Cl NH₂ H H H Br Cl NH-cyclopropyl H H H Br Cl OHH H H NH₂ Cl NH₂ H H H NH₂ Cl NH-cyclopropyl H H H NH₂ Cl OH H H H SH ClNH₂ H H H SH Cl NH-cyclopropyl H H H SH Cl OH acetyl H H H Cl NH₂ acetylH H H Cl NH-cyclopropyl acetyl H H H Cl OH acetyl H H F Cl NH₂ acetyl HH F Cl NH-cyclopropyl acetyl H H F Cl OH H acetyl acetyl H Cl NH₂ Hacetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H Cl OH acetyl acetylacetyl H Cl NH₂ acetyl acetyl acetyl H Cl NH-cyclopropyl acetyl acetylacetyl H Cl OH monophosphate acetyl acetyl H Cl NH₂ monophosphate acetylacetyl H Cl NH-cyclopropyl monophosphate acetyl acetyl H Cl OHdiphosphate acetyl acetyl H Cl NH₂ diphosphate acetyl acetyl H ClNH-cyclopropyl diphosphate acetyl acetyl H Cl OH triphosphate acetylacetyl H Cl NH₂ triphosphate acetyl acetyl H Cl NH-cyclopropyltriphosphate acetyl acetyl H Cl OH H H H H Cl NH₂ H H H H ClNH-cyclopropyl H H H H Cl OH H H H H Br NH₂ H H H H Br NH-cyclopropyl HH H H Br OH

indicates data missing or illegible when filed

Alternatively, the following nucleosides of Formula V are prepared,using the appropriate sugar and pyrimidine or purine bases.

(V)

wherein: R¹ R² R³ X¹ Y H H H H H H H H H NH₂ H H H H NH-cyclopropyl H HH H NH-methyl H H H H NH-ethyl H H H H NH-acetyl H H H H OH H H H H OMeH H H H OEt H H H H O-cyclopropyl H H H H O-acetyl H H H H SH H H H HSMe H H H H SEt H H H H S-cyclopropyl monophosphate H H H NH₂monophosphate H H H NH-acetyl monophosphate H H H NH-cyclopropylmonophosphate H H H NH-methyl monophosphate H H H NH-ethyl monophosphateH H H OH monophosphate H H H O-acetyl monophosphate H H H OMemonophosphate H H H OEt monophosphate H H H O-cyclopropyl monophosphateH H H SH monophosphate H H H SMe monophosphate H H H SEt monophosphate HH H S-cyclopropyl diphosphate H H H NH₂ diphosphate H H H NH-acetyldiphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl diphosphateH H H NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyldiphosphate H H H OMe diphosphate H H H OEt diphosphate H H HO-cyclopropyl diphosphate H H H SH diphosphate H H H SMe diphosphate H HH SEt diphosphate H H H S-cyclopropyl triphosphate H H H NH₂triphosphate H H H NH-acetyl triphosphate H H H NH-cyclopropyltriphosphate H H H NH-methyl triphosphate H H H NH-ethyl triphosphate HH H OH triphosphate H H H OMe triphosphate H H H OEt triphosphate H H HO-cyclopropyl triphosphate H H H O-acetyl triphosphate H H H SHtriphosphate H H H SMe triphosphate H H H SEt triphosphate H H HS-cyclopropyl monophosphate monophosphate monophosphate H NH₂monophosphate monophosphate monophosphate H NH-cyclopropyl monophosphatemonophosphate monophosphate H OH diphosphate diphosphate diphosphate HNH₂ diphosphate diphosphate diphosphate H NH-cyclopropyl diphosphatediphosphate diphosphate H OH triphosphate triphosphate triphosphate HNH₂ triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphatetriphosphate triphosphate H OH H H H F NH₂ H H H F NH-cyclopropyl H H HF OH H H H Cl NH₂ H H H Cl NH-cyclopropyl H H H CI OH H H H Br NH₂ H H HBr NH-cyclopropyl H H H Br OH H H H NH₂ NH₂ H H H NH₂ NH-cyclopropyl H HH NH₂ OH H H H SH NH₂ H H H SH NH-cyclopropyl H H H SH OH acetyl H H HNH₂ acetyl H H H NH-cyclopropyl acetyl H H H OH acetyl H H F NH₂ acetylH H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H NH₂ H acetylacetyl H NH-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H NH₂acetyl acetyl acetyl H NH-cyclopropyl acetyl acetyl acetyl H OHmonophosphate acetyl acetyl H NH₂ monophosphate acetyl acetyl HNH-cyclopropyl monophosphate acetyl acetyl H OH diphosphate acetylacetyl H NH₂ diphosphate acetyl acetyl H NH-cyclopropyl diphosphateacetyl acetyl H OH triphosphate acetyl acetyl H NH₂ triphosphate acetylacetyl H NH-cyclopropyl triphosphate acetyl acetyl H OH

Alternatively, the following nucleosides of Formula X are prepared,using the appropriate sugar and pyrimidine or purine bases.

(X)

wherein: R¹ R² R³ R⁶ X Base H H H CH₃ O 2,4-O- Diacetyluracil H H H CH₃O Hypoxanthine H H H CH₃ O 2,4-O- Diacetylthymine H H H CH₃ O Thymine HH H CH₃ O Cytosine H H H CH₃ O 4-(N-mono- acetyl)cytosine H H H CH₃ O4-(N,N- diacetyl)cytosine H H H CH₃ O Uracil H H H CH₃ O 5-FluorouracilH H H CH₃ S 2,4-O- Diacetyluraci H H H CH₃ S Hypoxanthine H H H CH₃ S2,4-O- Diacetylthymine H H H CH₃ S Thymine H H H CH₃ S Cytosine H H HCH₃ S 4-(N-mono- acetyl)cytosine H H H CH₃ S 4-(N,N- diacetyl)cytosine HH H CH₃ S Uracil H H H CH₃ S 5-Fluorouracil monophosphate H H CH₃ O2,4-O- Diacetyluracil monophosphate H H CH₃ O Hypoxanthine monophosphateH H CH₃ O 2,4-O- Diacetylthym monophosphate H H CH₃ O Thyminemonophosphate H H CH₃ O Cytosine monophosphate H H CH₃ O 4-(N-mono-acetyl)cytosine monophosphate H H CH₃ O 4-(N,N- diacetyl)cytosinemonophosphate H H CH₃ O Uracil monophosphate H H CH₃ O 5-Fluorouracilmonophosphate H H CH₃ S 2,4-O- Diacetyluracil monophosphate H H CH₃ SHypoxanthine monophosphate H H CH₃ S 2,4-O- Diacetylthym monophosphate HH CH₃ S Thymine monophosphate H H CH₃ S Cytosine monophosphate H H CH₃ S4-(N-mono- acetyl)cytosine monophosphate H H CH₃ S 4-(N,N-diacetyl)cytosine monophosphate H H CH₃ S Uracil monophosphate H H CH₃ S5-Fluorouracil diphosphate H H CH₃ O 2,4-O- Diacetyluracil diphosphate HH CH₃ O Hypoxanthine diphosphate H H CH₃ O 2,4-O- Diacetylthyminediphosphate H H CH₃ O Thymine diphosphate H H CH₃ O Cytosine diphosphateH H CH₃ O 4-(N-mono- acetyl)cytosine diphosphate H H CH₃ O 4-(N,N-diacetyl)cytosine diphosphate H H CH₃ O Uracil diphosphate H H CH₃ O5-Fluorouracil diphosphate H H CH₃ S 2,4-O- Diacetyluracil diphosphate HH CH₃ S Hypoxanthine diphosphate H H CH₃ S 2,4-O- Diacetylthymdiphosphate H H CH₃ S Thymine diphosphate H H CH₃ S Cytosinetriphosphate H H CH₃ O 2,4-O- Diacetyluracil triphosphate H H CH₃ OHypoxanthine triphosphate H H CH₃ O 2,4-O- Diacetylthymine triphosphateH H CH₃ O Thymine triphosphate H H CH₃ O Cytosine triphosphate H H CH₃ O4-(N-mono- acetyl)cytosine triphosphate H H CH₃ O 4-(N,N-diacetyl)cytosine triphosphate H H CH₃ O Uracil triphosphate H H CH₃ O5-Fluorouracil triphosphate H H CH₃ S 2,4-O- Diacetyluracil triphosphateH H CH₃ S Hypoxanthine triphosphate H H CH₃ S 2,4-O- Diacetylthyminetriphosphate H H CH₃ S Thymine triphosphate H H CH₃ S Cytosinemonophosphate monophosphate monophosphate CF₃ O 2,4-O- Diacetyluracilmonophosphate monophosphate monophosphate CF₃ O Hypoxanthinemonophosphate monophosphate monophosphate CF₃ O 2,4-O- Diacetylthyminemonophosphate monophosphate monophosphate CF₃ O Thymine monophosphatemonophosphate monophosphate CF₃ O Cytosine monophosphate monophosphatemonophosphate CF₃ O 4-(N-mono- acetyl)cytosine monophosphatemonophosphate monophosphate CF₃ O 4-(N,N- diacetyl)cytosinemonophosphate monophosphate monophosphate CF₃ O Uracil monophosphatemonophosphate monophosphate CF₃ O 5-Fluorouracil monophosphatemonophosphate monophosphate CF₃ S 2,4-O- Diacetyluracil monophosphatemonophosphate monophosphate CF₃ S Hypoxanthine monophosphatemonophosphate monophosphate CF₃ S 2,4-O- Diacetylthymine monophosphatemonophosphate monophosphate CF₃ S Thymine monophosphate monophosphatemonophosphate CF₃ S Cytosine monophosphate monophosphate monophosphateCF₃ S 4-(N-mono- acetyl)cytosine monophosphate monophosphatemonophosphate CF₃ S 4-(N,N- diacetyl)cytosine monophosphatemonophosphate monophosphate CF₃ S Uracil monophosphate monophosphatemonophosphate CF₃ S 5-Fluorouracil acetyl acetyl acetyl CF₃ O 4-(N,N-diacetyl)cytosine acetyl acetyl acetyl CF₃ S 4-(N,N- diacetyl)cytosineacetyl acetyl acetyl 2-bromo- O 4-(N,N- vinyl diacetyl)cytosine acetylacetyl acetyl 2-bromo- S 4-(N,N- vinyl diacetyl)cytosine H H H CH₃ O2-(N,N-diacetyl)- guanine H H H CH₃ O 6-O-acetyl guanine H H H CH₃ O8-fluoroguanine H H H CH₃ O guanine H H H CH₃ O 6-(N,N-diacetyl)-adenine H H H CH₃ O 2-fluoroadenine H H H CH₃ O 8-fluoroadenine H H HCH₃ O 2,8-difluoro- adenine H H H CH₃ O adenine H H H CH₃ S2-(N,N-diacetyl)- guanine H H H CH₃ S 6-O-acetyl guanine H H H CH₃ S8-fluoroguanine H H H CH₃ S guanine H H H CH₃ S 6-(N,N-diacetyl)-adenine H H H CH₃ S 2-fluoroadenine H H H CH₃ S 8-fluoroadenine H H HCH₃ S 2,8-difluoro- adenine H H H CH₃ S adenine monophosphate H H CH₃ O2-(N,N-diacetyl)- guanine monophosphate H H CH₃ O 6-O-acetyl guaninemonophosphate H H CH₃ O 8-fluoroguanine monophosphate H H CH₃ O guaninemonophosphate H H CH₃ O 6-(N,N-diacetyl)- adenine monophosphate H H CH₃O 2-fluoroadenine monophosphate H H CH₃ O 8-fluoroadenine monophosphateH H CH₃ O 2,8-difluoro- adenine monophosphate H H CH₃ O adeninemonophosphate H H CH₃ S 2-(N,N-diacetyl)- guanine monophosphate H H CH₃S 6-O-acetyl guanine monophosphate H H CH₃ S 8-fluoroguaninemonophosphate H H CH₃ S guanine monophosphate H H CH₃ S6-(N,N-diacetyl)- adenine monophosphate H H CH₃ S 2-fluoroadeninemonophosphate H H CH₃ S 8-fluoroadenine monophosphate H H CH₃ S2,8-difluoro- adenine monophosphate H H CH₃ S adenine diphosphate H HCH₃ O 2-(N,N-diacetyl)- guanine diphosphate H H CH₃ O 6-O-acetyl guaninediphosphate H H CH₃ O 8-fluoroguanine diphosphate H H CH₃ O guaninediphosphate H H CH₃ O 6-(N,N-diacetyl)- adenine diphosphate H H CH₃ O2-fluoroadenine diphosphate H H CH₃ O 8-fluoroadenine diphosphate H HCH₃ O 2,8-difluoro- adenine diphosphate H H CH₃ O adenine diphosphate HH CH₃ S 2-(N,N-diacetyl)- guanine diphosphate H H CH₃ S 6-O-acetylguanine diphosphate H H CH₃ S 8-fluoroguanine diphosphate H H CH₃ Sguanine diphosphate H H CH₃ S 6-(N,N-diacetyl)- adenine diphosphate H HCH₃ S 2-fluoroadenine diphosphate H H CH₃ S 8-fluoroadenine diphosphateH H CH₃ S 2,8-difluoro- adenine diphosphate H H CH₃ S adeninetriphosphate H H CH₃ O 2-(N,N-diacetyl)- guanine triphosphate H H CH₃ O6-O-acetyl guanine triphosphate H H CH₃ O 8-fluoroguanine triphosphate HH CH₃ O guanine triphosphate H H CH₃ O 6-(N,N-diacetyl)- adeninetriphosphate H H CH₃ O 2-fluoroadenine triphosphate H H CH₃ O8-fluoroadenine triphosphate H H CH₃ O 2,8-difluoro- adeninetriphosphate H H CH₃ O 2-(N,N-diacetyl)- guanine triphosphate H H CH₃ S6-O-acetyl guanine triphosphate H H CH₃ S 8-fluoroguanine triphosphate HH CH₃ S guanine triphosphate H H CH₃ S 6-(N,N-diacetyl)- adeninetriphosphate H H CH₃ S 2-fluoroadenine triphosphate H H CH₃ S8-fluoroadenine triphosphate H H CH₃ S 2,8-difluoro- adeninetriphosphate H H CH₃ S adenine monophosphate monophosphate monophosphateCF₃ O 2-(N,N-diacetyl)- guanine monophosphate monophosphatemonophosphate CF₃ O 6-O-acetyl guanine monophosphate monophosphatemonophosphate CF₃ O 8-fluoroguanine monophosphate monophosphatemonophosphate CF₃ O guanine monophosphate monophosphate monophosphateCF₃ O 6-(N,N-diacetyl)- adenine monophosphate monophosphatemonophosphate CF₃ O 2-fluoroadenine monophosphate monophosphatemonophosphate CF₃ O 8-fluoroadenine monophosphate monophosphatemonophosphate CF₃ O 2,8-difluoro- adenine monophosphate monophosphatemonophosphate CF₃ O adenine monophosphate monophosphate monophosphateCF₃ S 2-(N,N-diacetyl)- guanine monophosphate monophosphatemonophosphate CF₃ S 6-O-acetyl guanine monophosphate monophosphatemonophosphate CF₃ S 8-fluoroguanine monophosphate monophosphatemonophosphate CF₃ S guanine monophosphate monophosphate monophosphateCF₃ S 6-(N,N-diacetyl)- adenine monophosphate monophosphatemonophosphate CF₃ S 2-fluoroadenine monophosphate monophosphatemonophosphate CF₃ S 8-fluoroadenine monophosphate monophosphatemonophosphate CF₃ S 2,8-difluoro- adenine monophosphate monophosphatemonophosphate CF₃ S adenine acetyl acetyl acetyl CF₃ O guanine acetylacetyl acetyl CF₃ S guanine acetyl acetyl acetyl 2-bromo- O guaninevinyl acetyl acetyl acetyl 2-bromo- S guanine vinyl

Alternatively, the following nucleosides of Formula XI are prepared,using the appropriate sugar and pyrimidine or purine bases.

(XI)

wherein: R¹ R² R⁷ R⁶ X Base H H H CH₃ O 2,4-O-Diacetyluracil H H H CH₃ OHypoxanthine H H H CH₃ O 2,4-O-Diacetylthymine H H H CH₃ O Thymine H H HCH₃ O Cytosine H H H CH₃ O 4-(N-mono- acetyl)cytosine H H H CH₃ O4-(N,N-diacetyl)cytosine H H H CH₃ O Uracil H H H CH₃ O 5-Fluorouracil HH H CH₃ S 2,4-O-Diacetyluracil H H H CH₃ S Hypoxanthine H H H CH₃ S2,4-O-Diacetylthymine H H H CH₃ S Thymine H H H CH₃ S Cytosine H H H CH₃S 4-(N-mono-acetyl)cytosin H H H CH₃ S 4-(N,N-diacetyl)cytosine H H HCH₃ S Uracil H H H CH₃ S 5-Fluorouracil CH₃ monophosphate H H CH₃ O2,4-O-Diacetyluracil monophosphate H H CH₃ O Hypoxanthine monophosphateH H CH₃ O 2,4-O-Diacetylthymine monophosphate H H CH₃ O Thyminemonophosphate H H CH₃ O Cytosine monophosphate H H CH₃ O 4-(N-mono-acetyl)cytosine monophosphate H H CH₃ O 4-(N,N-diacetyl)cytosinemonophosphate H H CH₃ O Uracil monophosphate H H CH₃ O 5-Fluorouracilmonophosphate H H CH₃ S 2,4-O-Diacetyluracil monophosphate H H CH₃ SHypoxanthine monophosphate H H CH₃ S 2,4-O-Diacetylthymine monophosphateH H CH₃ S Thymine monophosphate H H CH₃ S Cytosine monophosphate H H CH₃S 4-(N-mono- acetyl)cytosine monophosphate H H CH₃ S4-(N,N-diacetyl)cytosine monophosphate H H CH₃ S Uracil monophosphate HH CH₃ S 5-Fluorouracil diphosphate H H CH₃ O 2,4-O-Diacetyluracdiphosphate H H CH₃ O Hypoxanthine diphosphate H H CH₃ O2,4-O-Diacetylthymine diphosphate H H CH₃ O Thymine diphosphate H H CH₃O Cytosine diphosphate H H CH₃ O 4-(N-mono- acetyl)cytosine diphosphateH H CH₃ O 4-(N,N-diacetyl)cytosine diphosphate H H CH₃ O Uracildiphosphate H H CH₃ O 5-Fluorouracil diphosphate H H CH₃ S2,4-O-Diacetyluracil diphosphate H H CH₃ S Hypoxanthine diphosphate H HCH₃ S 2,4-O-Diacetylthym diphosphate H H CH₃ S Thymine diphosphate H HCH₃ S Cytosine triphosphate H H CH₃ O 2,4-O-Diacetyluracil triphosphateH H CH₃ O Hypoxanthine triphosphate H H CH₃ O 2,4-O-Diacetylthyminetriphosphate H H CH₃ O Thymine triphosphate H H CH₃ O Cytosinetriphosphate H H CH₃ O 4-(N-mono- acetyl)cytosine triphosphate H H CH₃ O4-(N,N-diacetyl)cytos triphosphate H H CH₃ O Uracil triphosphate H H CH₃O 5-Fluorouracil triphosphate H H CH₃ S 2,4-O-Diacetyluraciltriphosphate H H CH₃ S Hypoxanthine triphosphate H H CH₃ S2,4-O-Diacetylthym triphosphate H H CH₃ S Thymine triphosphate H H CH₃ SCytosine monophosphate monophosphate Br CF₃ O 2,4-O-Diacetyluracilmonophosphate monophosphate Br CF₃ O Hypoxanthine monophosphatemonophosphate Br CF₃ O 2,4-O-Diacetylthymine monophosphate monophosphateBr CF₃ O Thymine monophosphate monophosphate Br CF₃ O Cytosinemonophosphate monophosphate Br CF₃ O 4-(N-mono- acetyl)cytosinemonophosphate monophosphate Br CF₃ O 4-(N,N-diacetyl)cytosinemonophosphate monophosphate Br CF₃ O Uracil monophosphate monophosphateBr CF₃ O 5-Fluorouracil monophosphate monophosphate Br CF₃ S2,4-O-Diacetyluracil monophosphate monophosphate Br CF₃ S Hypoxanthinemonophosphate monophosphate Br CF₃ S 2,4-O-Diacetylthymine monophosphatemonophosphate Br CF₃ S Thymine monophosphate monophosphate Br CF₃ SCytosine monophosphate monophosphate Br CF₃ S 4-(N-mono- acetyl)cytosinemonophosphate monophosphate Br CF₃ S 4-(N,N-diacetyl)cytos monophosphatemonophosphate Br CF₃ S Uracil monophosphate monophosphate Br CF₃ S5-Fluorouracil acetyl acetyl NO2 CF₃ O 4-(N,N-diacetyl)cytosine acetylacetyl NO2 CF₃ S 4-(N,N-diacetyl)cytosine acetyl acetyl NO2 CF₃ O4-(N,N-diacetyl)cytosine acetyl acetyl NO2 2-bromo- S4-(N,N-diacetyl)cytosine vinyl

Alternatively, the following nucleosides of Formula XII are prepared,using the appropriate sugar and pyrimidine or purine bases.

(XII)

R¹ R⁶ X Base H CH₃ O 2,4-O-Diacetyluracil H CH₃ O Hypoxanthine H CH₃ O2,4-O-Diacetylthymine H CH₃ O Thymine H CH₃ O Cytosine H CH₃ O4-(N-mono-acetyl)cytosine H CH₃ O 4-(N,N-diacetyl)cytosine H CH₃ OUracil H CH₃ O 5-Fluorouracil H CH₃ S 2,4-O-Diacetyluracil H CH₃ SHypoxanthine H CH₃ S 2,4-O-Diacetylthymine H CH₃ S Thymine H CH₃ SCytosine H CH₃ S 4-(N-mono-acetyl)cytosine H CH₃ S4-(N,N-diacetyl)cytosine H CH₃ S Uracil H CH₃ S 5-Fluorouracilmonophosphate CH₃ O 2,4-O-Diacetyluracil monophosphate CH₃ OHypoxanthine monophosphate CH₃ O 2,4-O-Diacetylthymine monophosphate CH₃O Thymine monophosphate CH₃ O Cytosine monophosphate CH₃ O4-(N-mono-acetyl)cytosine monophosphate CH₃ O 4-(N,N-diacetyl)cytosinemonophosphate CH₃ O Uracil monophosphate CH₃ O 5-Fluorouracilmonophosphate CH₃ S 2,4-O-Diacetyluracil monophosphate CH₃ SHypoxanthine monophosphate CH₃ S 2,4-O-Diacetylthymine monophosphate CH₃S Thymine monophosphate CH₃ S Cytosine monophosphate CH₃ S4-(N-mono-acetyl)cytosine monophosphate CH₃ S 4-(N,N-diacetyl)cytosinemonophosphate CH₃ S Uracil monophosphate CH₃ S 5-Fluorouracildiphosphate CH₃ O 2,4-O-Diacetyluracil diphosphate CH₃ O Hypoxanthinediphosphate CH₃ O 2,4-O-Diacetylthymine diphosphate CH₃ O Thyminediphosphate CH₃ O Cytosine diphosphate CH₃ O 4-(N-mono-acetyl)cytosinediphosphate CH₃ O 4-(N,N-diacetyl)cytosine diphosphate CH₃ O Uracildiphosphate CH₃ O 5-Fluorouracil diphosphate CH₃ S 2,4-O-Diacetyluracildiphosphate CH₃ S Hypoxanthine diphosphate CH₃ S 2,4-O-Diacetylthyminediphosphate CH₃ S Thymine diphosphate CH₃ S Cytosine triphosphate CH₃ O2,4-O-Diacetyluracil triphosphate CH₃ O Hypoxanthine triphosphate CH₃ O2,4-O-Diacetylthymine triphosphate CH₃ O Thymine triphosphate CH₃ OCytosine triphosphate CH₃ O 4-(N-mono-acetyl)cytosine triphosphate CH₃ O4-(N,N-diacetyl)cytosine triphosphate CH₃ O Uracil triphosphate CH₃ O5-Fluorouracil triphosphate CH₃ S 2,4-O-Diacetyluracil triphosphate CH₃S Hypoxanthine triphosphate CH₃ S 2,4-O-Diacetylthymine triphosphate CH₃S Thymine triphosphate CH₃ S Cytosine monophosphate CF₃ O2,4-O-Diacetyluracil monophosphate CF₃ O Hypoxanthine monophosphate CF₃O 2,4-O-Diacetylthymine monophosphate CF₃ O Thymine monophosphate CF₃ OCytosine monophosphate CF₃ O 4-(N-mono-acetyl)cytosine monophosphate CF₃O 4-(N,N-diacetyl)cytosine monophosphate CF₃ O Uracil monophosphate CF₃O 5-Fluorouracil monophosphate CF₃ S 2,4-O-Diacetyluracil monophosphateCF₃ S Hypoxanthine monophosphate CF₃ S 2,4-O-Diacetylthyminemonophosphate CF₃ S Thymine monophosphate CF₃ S Cytosine monophosphateCF₃ S 4-(N-mono-acetyl)cytosine monophosphate CF₃ S4-(N,N-diacetyl)cytosine monophosphate CF₃ S Uracil monophosphate CF₃ S5-Fluorouracil acetyl CF₃ O 4-(N,N-diacetyl)cytosine acetyl CF₃ S4-(N,N-diacetyl)cytosine acetyl 2-bromo-vinyl O 4-(N,N-diacetyl)cytosineacetyl 2-bromo-vinyl S 4-(N,N-diacetyl)cytosine

Alternatively, the following nucleosides of Formula XVII are prepared,using the appropriate sugar and pyrimidine or purine bases.

(XVII)

R¹ R⁶ R⁷ X Base R⁹ R¹⁰ H CH₃ H O 2,4-O-Diacetyluracil NHAc Me H CH₃ H OHypoxanthine NH2 Me H CH₃ H O 2,4-O-Diacetylthymine NHAc Me H CH₃ H OThymine NH2 Me H CH₃ H O Cytosine NH2 Me H CH₃ H O4-(N-mono-acetyl)cytosine NHAc Me H CH₃ H O 4-(N,N-diacetyl)cytosineNHAc Me H CH₃ H O Uracil NH2 Me H CH₃ H O 5-Fluorouracil NH2 Me H CH₃ HS 2,4-O-Diacetyluracil NHAc Me H CH₃ H S Hypoxanthine NH2 Me H CH₃ H S2,4-O-Diacetylthymine NHAc Me H CH₃ H S Thymine NH2 Me H CH₃ H SCytosine NH2 Me H CH₃ H S 4-(N-mono-acetyl)cytosine NHAc Me H CH₃ H S4-(N,N-diacetyl)cytosine NHAc Me H CH₃ H S Uracil NH2 Me H CH₃ H S5-Fluorouracil NH2 Me monophosphate CH₃ H O 2,4-O-Diacetyluracil NHAc Memonophosphate CH₃ H O Hypoxanthine NH2 Me monophosphate CH₃ H O2,4-O-Diacetylthymine NHAc Me monophosphate CH₃ H O Thymine NH2 Memonophosphate CH₃ H O Cytosine NH2 Me monophosphate CH₃ H O4-(N-mono-acetyl)cytosine NHAC Me monophosphate CH₃ H O4-(N,N-diacetyl)cytosine NHAc Me monophosphate CH₃ H O Uracil NH2 Memonophosphate CH₃ H O 5-Fluorouracil NH2 Me monophosphate CH₃ H S2,4-O-Diacetyluracil NHAc Me monophosphate CH₃ H S Hypoxanthine NH2 Memonophosphate CH₃ H S 2,4-O-Diacetylthymine NHAc Me monophosphate CH₃ HS Thymine NH2 Me monophosphate CH₃ H S Cytosine NH2 Me monophosphate CH₃H S 4-(N-mono-acetyl)cytosine NHAc Me monophosphate CH₃ H S4-(N,N-diacetyl)cytosine NHAc Me monophosphate CH₃ H S Uracil NH2 Memonophosphate CH₃ H S 5-Fluorouracil NH2 Me diphosphate CH₃ H O2,4-O-Diacetyluracil NHAc Me diphosphate CH₃ H O Hypoxanthine NH2 Mediphosphate CH₃ H O 2,4-O-Diacetylthymine NH2 Me diphosphate CH₃ H OThymine NH2 Me diphosphate CH₃ H O Cytosine NH2 Me diphosphate CH₃ H O4-(N-mono-acetyl)cytosine NHAc Me diphosphate CH₃ H O4-(N,N-diacetyl)cytos NHAc Me diphosphate CH₃ H O Uracil NH2 Mediphosphate CH₃ H O 5-Fluorouracil NH2 Me diphosphate CH₃ H S2,4-O-Diacetyluracil NH2 Me diphosphate CH₃ H S Hypoxanthine NH2 Mediphosphate CH₃ H S 2,4-O-Diacetylthymine NHAc Me diphosphate CH₃ H SThymine NH2 Me diphosphate CH₃ H S Cytosine NH2 Me triphosphate CH₃ H O2,4-O-Diacetyluracil NHAc Me triphosphate CH₃ H O Hypoxanthine NHAc Metriphosphate CH₃ H O 2,4-O-Diacetylthymine NHAc Me triphosphate CH₃ H OThymine NH2 Me triphosphate CH₃ H O Cytosine NH2 Me triphosphate CH₃ H O4-(N-mono-acetyl)cytosine NHAc Me triphosphate CH₃ H O4-(N,N-diacetyl)cytosine NH2 Me triphosphate CH₃ H O Uracil NH2 Metriphosphate CH₃ H O 5-Fluorouracil NH2 Me triphosphate CH₃ H S2,4-O-Diacetyluracil NH2 Me triphosphate CH₃ H S Hypoxanthine NH2 Metriphosphate CH₃ H S 2,4-O-Diacetylthymine NH2 Me triphosphate CH₃ H SThymine NH2 Me triphosphate CH₃ H S Cytosine NH2 Me monophosphate CF₃ HO 2,4-O-Diacetyluracil NH2 Me monophosphate CF₃ H O Hypoxanthine NH2 Memonophosphate CF₃ H O 2,4-O-Diacetylthymine NH2 Me monophosphate CF₃ H OThymine NH2 Me monophosphate CF₃ H O Cytosine NH2 Me monophosphate CF₃ HO 4-(N-mono-acetyl)cytosine NH2 Me monophosphate CF₃ H O4-(N,N-diacetyl)cytosine NH2 Me monophosphate CF₃ H O Uracil NH2 Memonophosphate CF₃ H O 5-Fluorouracil NH2 Me monophosphate CF₃ H S2,4-O-Diacetyluracil NH2 Me monophosphate CF₃ H S Hypoxanthine NH2 Memonophosphate CF₃ H S 2,4-O-Diacetylthymine NH2 Me monophosphate CF₃ H SThymine NH2 Me monophosphate CF₃ H S Cytosine NH2 Me monophosphate CF₃ HS 4-(N-mono-acetyl)cytosine NH2 Me monophosphate CF₃ H S4-(N,N-diacetyl)cytosine NH2 Me monophosphate CF₃ H S Uracil NH2 Memonophosphate CF₃ H S 5-Fluorouracil NH2 Me acetyl CH₃ H O4-(N,N-diacetyl)cytosine H Br acetyl CH₃ H S 4-(N,N-diacetyl)cytosine HBr acetyl CH₃ OH O 4-(N,N-diacetyl)cytosine H Br acetyl CH₃ OH S4-(N,N-diacetyl)cytosine H Br

Example 3 Preparation of 3′-C-methylriboadenine

The title compound can be prepared according to a published procedure(R. F. Nutt, M. J. Dickinson, F. W. Holly, and E. Walton,“Branched-chain sugar nucleosides. III. 3′-C-methyladenine”, J. Org.Chem. 1968, 33, 1789-1795) (Scheme 9).

In a similar manner, but using the appropriate sugar and pyrimidine orpurine bases, the following nucleosides of Formula III are prepared.

(III)

R¹ R² R³ X¹ X² Y H H H H H H H H H H H NH₂ H H H H H NH-cyclopropyl H HH H H NH-methyl H H H H H NH-ethyl H H H H H NH-acetyl H H H H H OH H HH H H OMe H H H H H OEt H H H H H O-cyclopropyl H H H H H O-acetyl H H HH H SH H H H H H SMe H H H H H SEt H H H H H S-cyclopropyl H H H H H F HH H H H Cl H H H H H Br H H H H H I monophosphate H H H H NH₂monophosphate H H H H NH-acetyl monophosphate H H H H NH-cyclopropylmonophosphate H H H H NH-methyl monophosphate H H H H NH-ethylmonophosphate H H H H OH monophosphate H H H H O-acetyl monophosphate HH H H OMe monophosphate H H H H OEt monophosphate H H H H O-cyclopropylmonophosphate H H H H SH monophosphate H H H H SMe monophosphate H H H HSEt monophosphate H H H H S-cyclopropyl monophosphate H H H H Fmonophosphate H H H H Cl monophosphate H H H H Br monophosphate H H H HI diphosphate H H H H NH₂ diphosphate H H H H NH-acetyl diphosphate H HH H NH-cyclopropyl diphosphate H H H H NH-methyl diphosphate H H H HNH-ethyl diphosphate H H H H OH diphosphate H H H H O-acetyl diphosphateH H H H OMe diphosphate H H H H OEt diphosphate H H H H O-cyclopropyldiphosphate H H H H SH diphosphate H H H H SMe diphosphate H H H H SEtdiphosphate H H H H S-cyclopropyl diphosphate H H H H F diphosphate H HH H Cl diphosphate H H H H Br diphosphate H H H H I triphosphate H H H HNH₂ triphosphate H H H H NH-acetyl triphosphate H H H H NH-cyclopropyltriphosphate H H H H NH-methyl triphosphate H H H H NH-ethyltriphosphate H H H H OH triphosphate H H H H OMe triphosphate H H H HOEt triphosphate H H H H O-cyclopropyl triphosphate H H H H O-acetyltriphosphate H H H H SH triphosphate H H H H SMe triphosphate H H H HSEt triphosphate H H H H S-cyclopropyl triphosphate H H H H Ftriphosphate H H H H Cl triphosphate H H H H Br triphosphate H H H H Imonophosphate monophosphate monophosphate H H NH₂ monophosphatemonophosphate monophosphate H H NH-cyclopropyl monophosphatemonophosphate monophosphate H H OH monophosphate monophosphatemonophosphate H H F monophosphate monophosphate monophosphate H H Cldiphosphate diphosphate diphosphate H H NH₂ diphosphate diphosphatediphosphate H H NH-cyclopropyl diphosphate diphosphate diphosphate H HOH diphosphate diphosphate diphosphate H H F diphosphate diphosphatediphosphate H H Cl triphosphate triphosphate triphosphate H H NH₂triphosphate triphosphate triphosphate H H NH-cyclopropyl triphosphatetriphosphate triphosphate H H OH triphosphate triphosphate triphosphateH H F triphosphate triphosphate triphosphate H H Cl H H H F H NH₂ H H HF H NH-cyclopropyl H H H F H OH H H H F H F H H H F H Cl H H H Cl H NH₂H H H Cl H NH-cyclopropyl H H H Cl H OH H H H Cl H F H H H Cl H Cl H H HBr H NH₂ H H H Br H NH-cyclopropyl H H H Br H OH H H H Br H F H H H Br HCl H H H NH₂ H NH₂ H H H NH₂ H NH-cyclopropyl H H H NH₂ H OH H H H NH₂ HF H H H NH₂ H Cl H H H SH H NH₂ H H H SH H NH-cyclopropyl H H H SH H OHH H H SH H F H H H SH H Cl acetyl H H H H NH₂ acetyl H H H HNH-cyclopropyl acetyl H H H H OH acetyl H H H H F acetyl H H H H Clacetyl H H F H NH₂ acetyl H H F H NH-cyclopropyl acetyl H H F H OHacetyl H H F H F acetyl H H F H Cl H acetyl acetyl H H NH₂ H acetylacetyl H H NH-cyclopropyl H acetyl acetyl H H OH H acetyl acetyl H H F Hacetyl acetyl H H Cl acetyl acetyl acetyl H H NH₂ acetyl acetyl acetyl HH NH-cyclopropyl acetyl acetyl acetyl H H OH acetyl acetyl acetyl H H Facetyl acetyl acetyl H H Cl monophosphate acetyl acetyl H H NH₂monophosphate acetyl acetyl H H NH-cyclopropyl monophosphate acetylacetyl H H OH monophosphate acetyl acetyl H H F monophosphate acetylacetyl H H Cl diphosphate acetyl acetyl H H NH₂ diphosphate acetylacetyl H H NH-cyclopropyl diphosphate acetyl acetyl H H OH diphosphateacetyl acetyl H H F diphosphate acetyl acetyl H H Cl triphosphate acetylacetyl H H NH₂ triphosphate acetyl acetyl H H NH-cyclopropyltriphosphate acetyl acetyl H H OH triphosphate acetyl acetyl H H Ftriphosphate acetyl acetyl H H Cl H H H H NH₂ H H H H H NH₂ NH₂ H H H HNH₂ NH-cyclopropyl H H H H NH₂ NH-methyl H H H H NH₂ NH-ethyl H H H HNH₂ NH-acetyl H H H H NH₂ OH H H H H NH₂ OMe H H H H NH₂ OEt H H H H NH₂O-cyclopropyl H H H H NH₂ O-acetyl H H H H NH₂ SH H H H H NH₂ SMe H H HH NH₂ SEt H H H H NH₂ S-cyclopropyl H H H H NH₂ F H H H H NH₂ Cl H H H HNH₂ Br H H H H NH₂ I monophosphate H H H NH₂ NH₂ monophosphate H H H NH₂NH-acetyl monophosphate H H H NH₂ NH-cyclopropyl monophosphate H H H NH₂NH-methyl monophosphate H H H NH₂ NH-ethyl monophosphate H H H NH₂ OHmonophosphate H H H NH₂ O-acetyl monophosphate H H H NH₂ OMemonophosphate H H H NH₂ OEt monophosphate H H H NH₂ O-cyclopropylmonophosphate H H H NH₂ SH monophosphate H H H NH₂ SMe monophosphate H HH NH₂ SEt monophosphate H H H NH₂ S-cyclopropyl monophosphate H H H NH₂F monophosphate H H H NH₂ Cl monophosphate H H H NH₂ Br monophosphate HH H NH₂ I diphosphate H H H NH₂ NH₂ diphosphate H H H NH₂ NH-acetyldiphosphate H H H NH₂ NH-cyclopropyl diphosphate H H H NH₂ NH-methyldiphosphate H H H NH₂ NH-ethyl diphosphate H H H NH₂ OH diphosphate H HH NH₂ O-acetyl diphosphate H H H NH₂ OMe diphosphate H H H NH₂ OEtdiphosphate H H H NH₂ O-cyclopropyl diphosphate H H H NH₂ SH diphosphateH H H NH₂ SMe diphosphate H H H NH₂ SEt diphosphate H H H NH₂S-cyclopropyl diphosphate H H H NH₂ F diphosphate H H H NH₂ Cldiphosphate H H H NH₂ Br diphosphate H H H NH₂ I triphosphate H H H NH₂NH₂ triphosphate H H H NH₂ NH-acetyl triphosphate H H H NH₂NH-cyclopropyl triphosphate H H H NH₂ NH-methyl triphosphate H H H NH₂NH-ethyl triphosphate H H H NH₂ OH triphosphate H H H NH₂ OMetriphosphate H H H NH₂ OEt triphosphate H H H NH₂ O-cyclopropyltriphosphate H H H NH₂ O-acetyl triphosphate H H H NH₂ SH triphosphate HH H NH₂ SMe triphosphate H H H NH₂ SEt triphosphate H H H NH₂S-cyclopropyl triphosphate H H H NH₂ F triphosphate H H H NH₂ Cltriphosphate H H H NH₂ Br triphosphate H H H NH₂ I monophosphatemonophosphate monophosphate H NH₂ NH₂ monophosphate monophosphatemonophosphate H NH₂ NH-cyclopropyl monophosphate monophosphatemonophosphate H NH₂ OH monophosphate monophosphate monophosphate H NH₂ Fmonophosphate monophosphate monophosphate H NH₂ Cl diphosphatediphosphate diphosphate H NH₂ NH₂ diphosphate diphosphate diphosphate HNH₂ NH-cyclopropyl diphosphate diphosphate diphosphate H NH₂ OHdiphosphate diphosphate diphosphate H NH₂ F diphosphate diphosphatediphosphate H NH₂ Cl triphosphate triphosphate triphosphate H NH₂ NH₂triphosphate triphosphate triphosphate H NH₂ NH-cyclopropyl triphosphatetriphosphate triphosphate H NH₂ OH triphosphate triphosphatetriphosphate H NH₂ F triphosphate triphosphate triphosphate H NH₂ Cl H HH F NH₂ NH₂ H H H F NH₂ NH-cyclopropyl H H H F NH₂ OH H H H F NH₂ F H HH F NH₂ Cl H H H Cl NH₂ NH₂ H H H Cl NH₂ NH-cyclopropyl H H H Cl NH₂ OHH H H Cl NH₂ F H H H Cl NH₂ Cl H H H Br NH₂ NH₂ H H H Br NH₂NH-cyclopropyl H H H Br NH₂ OH H H H Br NH₂ F H H H Br NH₂ Cl H H H NH₂NH₂ NH₂ H H H NH₂ NH₂ NH-cyclopropyl H H H NH₂ NH₂ OH H H H NH₂ NH₂ F HH H NH₂ NH₂ Cl H H H SH NH₂ NH₂ H H H SH NH₂ NH-cyclopropyl H H H SH NH₂OH H H H SH NH₂ F H H H SH NH₂ Cl acetyl H H H NH₂ NH₂ acetyl H H H NH₂NH-cyclopropyl acetyl H H H NH₂ OH acetyl H H H NH₂ F acetyl H H H NH₂Cl acetyl H H F NH₂ NH₂ acetyl H H F NH₂ NH-cyclopropyl acetyl H H F NH₂OH acetyl H H F NH₂ F acetyl H H F NH₂ Cl H acetyl acetyl H NH₂ NH₂ Hacetyl acetyl H NH₂ NH-cyclopropyl H acetyl acetyl H NH₂ OH H acetylacetyl H NH₂ F H acetyl acetyl H NH₂ Cl acetyl acetyl acetyl H NH₂ NH₂acetyl acetyl acetyl H NH₂ NH-cyclopropyl acetyl acetyl acetyl H NH₂ OHacetyl acetyl acetyl H NH₂ F acetyl acetyl acetyl H NH₂ Cl monophosphateacetyl acetyl H NH₂ NH₂ monophosphate acetyl acetyl H NH₂ NH-cyclopropylmonophosphate acetyl acetyl H NH₂ OH monophosphate acetyl acetyl H NH₂ Fmonophosphate acetyl acetyl H NH₂ Cl diphosphate acetyl acetyl H NH₂ NH₂diphosphate acetyl acetyl H NH₂ NH-cyclopropyl diphosphate acetyl acetylH NH₂ OH diphosphate acetyl acetyl H NH₂ F diphosphate acetyl acetyl HNH₂ Cl triphosphate acetyl acetyl H NH₂ NH₂ triphosphate acetyl acetyl HNH₂ NH-cyclopropyl triphosphate acetyl acetyl H NH₂ OH triphosphateacetyl acetyl H NH₂ F triphosphate acetyl acetyl H NH₂ Cl H H H H Cl H HH H H Cl H H H H H Cl NH₂ H H H H Cl NH-cyclopropyl H H H H Cl NH-methylH H H H Cl NH-ethyl H H H H Cl NH-acetyl H H H H Cl OH H H H H Cl OMe HH H H Cl OEt H H H H Cl O-cyclopropyl H H H H Cl O-acetyl H H H H Cl SHH H H H Cl SMe H H H H Cl SEt H H H H Cl S-cyclopropyl monophosphate H HH Cl NH₂ monophosphate H H H Cl NH-acetyl monophosphate H H H ClNH-cyclopropyl monophosphate H H H Cl NH-methyl monophosphate H H H ClNH-ethyl monophosphate H H H Cl OH monophosphate H H H Cl O-acetylmonophosphate H H H Cl OMe monophosphate H H H Cl OEt monophosphate H HH Cl O-cyclopropyl monophosphate H H H Cl SH monophosphate H H H Cl SMemonophosphate H H H Cl SEt monophosphate H H H Cl S-cyclopropyldiphosphate H H H Cl NH₂ diphosphate H H H Cl NH-acetyl diphosphate H HH Cl NH-cyclopropyl diphosphate H H H Cl NH-methyl diphosphate H H H ClNH-ethyl diphosphate H H H Cl OH diphosphate H H H Cl O-acetyldiphosphate H H H Cl OMe diphosphate H H H Cl OEt diphosphate H H H ClO-cyclopropyl diphosphate H H H Cl SH diphosphate H H H Cl SMediphosphate H H H Cl SEt diphosphate H H H Cl S-cyclopropyl triphosphateH H H Cl NH₂ triphosphate H H H Cl NH-acetyl triphosphate H H H ClNH-cyclopropyl triphosphate H H H Cl NH-methyl triphosphate H H H ClNH-ethyl triphosphate H H H Cl OH triphosphate H H H Cl OMe triphosphateH H H Cl OEt triphosphate H H H Cl O-cyclopropyl triphosphate H H H ClO-acetyl triphosphate H H H Cl SH triphosphate H H H Cl SMe triphosphateH H H Cl SEt triphosphate H H H Cl S-cyclopropyl monophosphatemonophosphate monophosphate H Cl NH₂ monophosphate monophosphatemonophosphate H Cl NH-cyclopropyl monophosphate monophosphatemonophosphate H Cl OH diphosphate diphosphate diphosphate H Cl NH₂diphosphate diphosphate diphosphate H Cl NH-cyclopropyl diphosphatediphosphate diphosphate H Cl OH triphosphate triphosphate triphosphate HCl NH₂ triphosphate triphosphate triphosphate H Cl NH-cyclopropyltriphosphate triphosphate triphosphate H Cl OH H H H F Cl NH₂ H H H F ClNH-cyclopropyl H H H F Cl OH H H H Cl Cl NH₂ H H H Cl Cl NH-cyclopropylH H H Cl Cl OH H H H Br Cl NH₂ H H H Br Cl NH-cyclopropyl H H H Br Cl OHH H H NH₂ Cl NH₂ H H H NH₂ Cl NH-cyclopropyl H H H NH₂ Cl OH H H H SH ClNH₂ H H H SH Cl NH-cyclopropyl H H H SH Cl OH acetyl H H H Cl NH₂ acetylH H H Cl NH-cyclopropyl acetyl H H H Cl OH acetyl H H F Cl NH₂ acetyl HH F Cl NH-cyclopropyl acetyl H H F Cl OH H acetyl acetyl H Cl NH₂ Hacetyl acetyl H Cl NH-cyclopropyl H acetyl acetyl H Cl OH acetyl acetylacetyl H Cl NH₂ acetyl acetyl acetyl H Cl NH-cyclopropyl acetyl acetylacetyl H Cl OH monophosphate acetyl acetyl H Cl NH₂ monophosphate acetylacetyl H Cl NH-cyclopropyl monophosphate acetyl acetyl H Cl OHdiphosphate acetyl acetyl H Cl NH₂ diphosphate acetyl acetyl H ClNH-cyclopropyl diphosphate acetyl acetyl H Cl OH triphosphate acetylacetyl H Cl NH₂ triphosphate acetyl acetyl H Cl NH-cyclopropyltriphosphate acetyl acetyl H Cl OH H H H H Cl NH₂ H H H H ClNH-cyclopropyl H H H H Cl OH H H H H Br NH₂ H H H H Br NH-cyclopropyl HH H H Br OH

Alternatively, the following nucleosides of Formula VI are prepared,using the appropriate sugar and pyrimidine or purine bases.

(VI)

R¹ R² R³ X¹ Y H H H H H H H H H NH₂ H H H H NH-cyclopropyl H H H HNH-methyl H H H H NH-ethyl H H H H NH-acetyl H H H H OH H H H H OMe H HH H OEt H H H H O-cyclopropyl H H H H O-acetyl H H H H SH H H H H SMe HH H H SEt H H H H S-cyclopropyl monophosphate H H H NH₂ monophosphate HH H NH-acetyl monophosphate H H H NH-cyclopropyl monophosphate H H HNH-methyl monophosphate H H H NH-ethyl monophosphate H H H OHmonophosphate H H H O-acetyl monophosphate H H H OMe monophosphate H H HOEt monophosphate H H H O-cyclopropyl monophosphate H H H SHmonophosphate H H H SMe monophosphate H H H SEt monophosphate H H HS-cyclopropyl diphosphate H H H NH₂ diphosphate H H H NH-acetyldiphosphate H H H NH-cyclopropyl diphosphate H H H NH-methyl diphosphateH H H NH-ethyl diphosphate H H H OH diphosphate H H H O-acetyldiphosphate H H H OMe diphosphate H H H OEt diphosphate H H HO-cyclopropyl diphosphate H H H SH diphosphate H H H SMe diphosphate H HH SEt diphosphate H H H S-cyclopropyl triphosphate H H H NH₂triphosphate H H H NH-acetyl triphosphate H H H NH-cyclopropyltriphosphate H H H NH-methyl triphosphate H H H NH-ethyl triphosphate HH H OH triphosphate H H H OMe triphosphate H H H OEt triphosphate H H HO-cyclopropyl triphosphate H H H O-acetyl triphosphate H H H SHtriphosphate H H H SMe triphosphate H H H SEt triphosphate H H HS-cyclopropyl monophosphate monophosphate monophosphate H NH₂monophosphate monophosphate monophosphate H NH-cyclopropyl monophosphatemonophosphate monophosphate H OH diphosphate diphosphate diphosphate HNH₂ diphosphate diphosphate diphosphate H NH-cyclopropyl diphosphatediphosphate diphosphate H OH triphosphate triphosphate triphosphate HNH₂ triphosphate triphosphate triphosphate H NH-cyclopropyl triphosphatetriphosphate triphosphate H OH H H H F NH₂ H H H F NH-cyclopropyl H H HF OH H H H Cl NH₂ H H H Cl NH-cyclopropyl H H H Cl OH H H H Br NH₂ H H HBr NH-cyclopropyl H H H Br OH H H H NH₂ NH₂ H H H NH₂ NH-cyclopropyl H HH NH₂ OH H H H SH NH₂ H H H SH NH-cyclopropyl H H H SH OH acetyl H H HNH₂ acetyl H H H NH-cyclopropyl acetyl H H H OH acetyl H H F NH₂ acetylH H F NH-cyclopropyl acetyl H H F OH H acetyl acetyl H NH₂ H acetylacetyl H NH-cyclopropyl H acetyl acetyl H OH acetyl acetyl acetyl H NH₂acetyl acetyl acetyl H NH-cyclopropyl acetyl acetyl acetyl H OHmonophosphate acetyl acetyl H NH₂ monophosphate acetyl acetyl HNH-cyclopropyl monophosphate acetyl acetyl H OH diphosphate acetylacetyl H NH₂ diphosphate acetyl acetyl H NH-cyclopropyl diphosphateacetyl acetyl H OH triphosphate acetyl acetyl H NH₂ triphosphate acetylacetyl H NH-cyclopropyl triphosphate acetyl acetyl H OH

Alternatively, the following nucleosides of Formula XIII are prepared,using the appropriate sugar and pyrimidine or purine bases.

(XIII)

R¹ R² R³ R⁶ X Base H H H CH₃ O 2,4-O- Diacetyluracil H H H CH₃ OHypoxanthine H H H CH₃ O 2,4-O- Diacetylthymine H H H CH₃ O Thymine H HH CH₃ O Cytosine H H H CH₃ O 4-(N-mono- acetyl)cytosine H H H CH₃ O4-(N,N- diacetyl)cytosine H H H CH₃ O Uracil H H H CH₃ O 5-FluorouracilH H H CH₃ S 2,4-O- Diacetyluraci H H H CH₃ S Hypoxanthine H H H CH₃ S2,4-O- Diacetylthymine H H H CH₃ S Thymine H H H CH₃ S Cytosine H H HCH₃ S 4-(N-mono- acetyl)cytosine H H H CH₃ S 4-(N,N- diacetyl)cytosine HH H CH₃ S Uracil H H H CH₃ S 5-Fluorouracil monophosphate H H CH₃ O2,4-O- Diacetyluracil monophosphate H H CH₃ O Hypoxanthine monophosphateH H CH₃ O 2,4-O- Diacetylthym monophosphate H H CH₃ O Thyminemonophosphate H H CH₃ O Cytosine monophosphate H H CH₃ O 4-(N-mono-acetyl)cytosine monophosphate H H CH₃ O 4-(N,N- diacetyl)cytosinemonophosphate H H CH₃ O Uracil monophosphate H H CH₃ O 5-Fluorouracilmonophosphate H H CH₃ S 2,4-O- Diacetyluracil monophosphate H H CH₃ SHypoxanthine monophosphate H H CH₃ S 2,4-O- Diacetylthym monophosphate HH CH₃ S Thymine monophosphate H H CH₃ S Cytosine monophosphate H H CH₃ S4-(N-mono- acetyl)cytosine monophosphate H H CH₃ S 4-(N,N-diacetyl)cytosine monophosphate H H CH₃ S Uracil monophosphate H H CH₃ S5-Fluorouracil diphosphate H H CH₃ O 2,4-O- Diacetyluracil diphosphate HH CH₃ O Hypoxanthine diphosphate H H CH₃ O 2,4-O- Diacetylthyminediphosphate H H CH₃ O Thymine diphosphate H H CH₃ O Cytosine diphosphateH H CH₃ O 4-(N-mono- acetyl)cytosine diphosphate H H CH₃ O 4-(N,N-diacetyl)cytosine diphosphate H H CH₃ O Uracil diphosphate H H CH₃ O5-Fluorouracil diphosphate H H CH₃ S 2,4-O- Diacetyluracil diphosphate HH CH₃ S Hypoxanthine diphosphate H H CH₃ S 2,4-O- Diacetylthymdiphosphate H H CH₃ S Thymine diphosphate H H CH₃ S Cytosinetriphosphate H H CH₃ O 2,4-O- Diacetyluracil triphosphate H H CH₃ OHypoxanthine triphosphate H H CH₃ O 2,4-O- Diacetylthymine triphosphateH H CH₃ O Thymine triphosphate H H CH₃ O Cytosine triphosphate H H CH₃ O4-(N-mono- acetyl)cytosine triphosphate H H CH₃ O 4-(N,N-diacetyl)cytosine triphosphate H H CH₃ O Uracil triphosphate H H CH₃ O5-Fluorouracil triphosphate H H CH₃ S 2,4-O- Diacetyluracil triphosphateH H CH₃ S Hypoxanthine triphosphate H H CH₃ S 2,4-O- Diacetylthyminetriphosphate H H CH₃ S Thymine triphosphate H H CH₃ S Cytosinemonophosphate mono- mono- CF₃ O 2,4-O- phosphate phosphateDiacetyluracil monophosphate mono- mono- CF₃ O Hypoxanthine phosphatephosphate monophosphate mono- mono- CF₃ O 2,4-O- phosphate phosphateDiacetylthymine monophosphate mono- mono- CF₃ O Thymine phosphatephosphate monophosphate mono- mono- CF₃ O Cytosine phosphate phosphatemonophosphate mono- mono- CF₃ O 4-(N-mono- phosphate phosphateacetyl)cytosine monophosphate mono- mono- CF₃ O 4-(N,N- phosphatephosphate diacetyl)cytosine monophosphate mono- mono- CF₃ O Uracilphosphate phosphate monophosphate mono- mono- CF₃ O 5-Fluorouracilphosphate phosphate monophosphate mono- mono- CF₃ S 2,4-O- phosphatephosphate Diacetyluracil monophosphate mono- mono- CF₃ S Hypoxanthinephosphate phosphate monophosphate mono- mono- CF₃ S 2,4-O- phosphatephosphate Diacetylthymine monophosphate mono- mono- CF₃ S Thyminephosphate phosphate monophosphate mono- mono- CF₃ S Cytosine phosphatephosphate monophosphate mono- mono- CF₃ S 4-(N-mono- phosphate phosphateacetyl)cytosine monophosphate mono- mono- CF₃ S 4-(N,N- phosphatephosphate diacetyl)cytosine monophosphate mono- mono- CF₃ S Uracilphosphate phosphate monophosphate mono- mono- CF₃ S 5-Fluorouracilphosphate phosphate acetyl acetyl acetyl CF₃ O 4-(N,N- diacetyl)cytosineacetyl acetyl acetyl CF₃ S 4-(N,N- diacetyl)cytosine acetyl acetylacetyl 2- O 4-(N,N- bromo- diacetyl)cytosine vinyl acetyl acetyl acetyl2- S 4-(N,N- bromo- diacetyl)cytosine vinyl H H H CH₃ O 2-(N,N-diacetyl)guanine H H H CH₃ O 6-O-acetyl guanine H H H CH₃ O8-fluoroguanine H H H CH₃ O guanine H H H CH₃ O 6-(N,N- diacetyl)adenineH H H CH₃ O 2-fluoroadenine H H H CH₃ O 8-fluoroadenine H H H CH₃ O2,8-difluoro- adenine H H H CH₃ O adenine H H H CH₃ S 2-(N,N-diacetyl)guanine H H H CH₃ S 6-O-acetyl guanine H H H CH₃ S8-fluoroguanine H H H CH₃ S guanine H H H CH₃ S 6-(N,N- diacetyl)adenineH H H CH₃ S 2-fluoroadenine H H H CH₃ S 8-fluoroadenine H H H CH₃ S2,8-difluoro- adenine H H H CH₃ S adenine monophosphate H H CH₃ O2-(N,N- diacetyl)guanine monophosphate H H CH₃ O 6-O-acetyl guaninemonophosphate H H CH₃ O 8-fluoroguanine monophosphate H H CH₃ O guaninemonophosphate H H CH₃ O 6-(N,N- diacetyl)adenine monophosphate H H CH₃ O2-fluoroadenine monophosphate H H CH₃ O 8-fluoroadenine monophosphate HH CH₃ O 2,8-difluoro- adenine monophosphate H H CH₃ O adeninemonophosphate H H CH₃ S 2-(N,N- diacetyl)guanine monophosphate H H CH₃ S6-O-acetyl guanine monophosphate H H CH₃ S 8-fluoroguanine monophosphateH H CH₃ S guanine monophosphate H H CH₃ S 6-(N,N- diacetyl)adeninemonophosphate H H CH₃ S 2-fluoroadenine monophosphate H H CH₃ S8-fluoroadenine monophosphate H H CH₃ S 2,8-difluoro- adeninemonophosphate H H CH₃ S adenine diphosphate H H CH₃ O 2-(N,N-diacetyl)guanine diphosphate H H CH₃ O 6-O-acetyl guanine diphosphate HH CH₃ O 8-fluoroguanine diphosphate H H CH₃ O guanine diphosphate H HCH₃ O 6-(N,N- diacetyl)adenine diphosphate H H CH₃ O 2-fluoroadeninediphosphate H H CH₃ O 8-fluoroadenine diphosphate H H CH₃ O2,8-difluoro- adenine diphosphate H H CH₃ O adenine diphosphate H H CH₃S 2-(N,N- diacetyl)guanine diphosphate H H CH₃ S 6-O-acetyl guaninediphosphate H H CH₃ S 8-fluoroguanine diphosphate H H CH₃ S guaninediphosphate H H CH₃ S 6-(N,N- diacetyl)adenine diphosphate H H CH₃ S2-fluoroadenine diphosphate H H CH₃ S 8-fluoroadenine diphosphate H HCH₃ S 2,8-difluoro- adenine diphosphate H H CH₃ S adenine triphosphate HH CH₃ O 2-(N,N- diacetyl)guanine triphosphate H H CH₃ O 6-O-acetylguanine triphosphate H H CH₃ O 8-fluoroguanine triphosphate H H CH₃ Oguanine triphosphate H H CH₃ O 6-(N,N- diacetyl)adenine triphosphate H HCH₃ O 2-fluoroadenine triphosphate H H CH₃ O 8-fluoroadeninetriphosphate H H CH₃ O 2,8-difluoro- adenine triphosphate H H CH₃ O2-(N,N- diacetyl)guanine triphosphate H H CH₃ S 6-O-acetyl guaninetriphosphate H H CH₃ S 8-fluoroguanine triphosphate H H CH₃ S guaninetriphosphate H H CH₃ S 6-(N,N- diacetyl)adenine triphosphate H H CH₃ S2-fluoroadenine triphosphate H H CH₃ S 8-fluoroadenine triphosphate H HCH₃ S 2,8-difluoro- adenine triphosphate H H CH₃ S adenine monophosphatemono- mono- CF₃ O 2-(N,N- phosphate phosphate diacetyl)guaninemonophosphate mono- mono- CF₃ O 6-O-acetyl phosphate phosphate guaninemonophosphate mono- mono- CF₃ O 8-fluoroguanine phosphate phosphatemonophosphate mono- mono- CF₃ O guanine phosphate phosphatemonophosphate mono- mono- CF₃ O 6-(N,N- phosphate phosphatediacetyl)adenine monophosphate mono- mono- CF₃ O 2-fluoroadeninephosphate phosphate monophosphate mono- mono- CF₃ O 8-fluoroadeninephosphate phosphate monophosphate mono- mono- CF₃ O 2,8-difluoro-phosphate phosphate adenine monophosphate mono- mono- CF₃ O adeninephosphate phosphate monophosphate mono- mono- CF₃ S 2-(N,N- phosphatephosphate diacetyl)guanine monophosphate mono- mono- CF₃ S 6-O-acetylphosphate phosphate guanine monophosphate mono- mono- CF₃ S8-fluoroguanine phosphate phosphate monophosphate mono- mono- CF₃ Sguanine phosphate phosphate monophosphate mono- mono- CF₃ S 6-(N,N-phosphate phosphate diacetyl)adenine monophosphate mono- mono- CF₃ S2-fluoroadenine phosphate phosphate monophosphate mono- mono- CF₃ S8-fluoroadenine phosphate phosphate monophosphate mono- mono- CF₃ S2,8-difluoro- phosphate phosphate adenine monophosphate mono- mono- CF₃S adenine phosphate phosphate acetyl acetyl acetyl CF₃ O guanine acetylacetyl acetyl CF₃ S guanine acetyl acetyl acetyl 2- O guanine bromo-vinyl acetyl acetyl acetyl 2- S guanine bromo- vinyl

Alternatively, the following nucleosides of Formula XIV are prepared,using the appropriate sugar and pyrimidine or purine bases.

(XIV)

R¹ R² R⁶ X Base H H CH₃ O 2,4-O-Diacetyluracil H H CH₃ O Hypoxanthine HH CH₃ O 2,4-O-Diacetylthymine H H CH₃ O Thymine H H CH₃ O Cytosine H HCH₃ O 4-(N-mono-acetyl)cytosine H H CH₃ O 4-(N,N-diacetyl)cytosine H HCH₃ O Uracil H H CH₃ O 5-Fluorouracil H H CH₃ S 2,4-O-Diacetyluracil H HCH₃ S Hypoxanthine H H CH₃ S 2,4-O-Diacetylthymine H H CH₃ S Thymine H HCH₃ S Cytosine H H CH₃ S 4-(N-mono-acetyl)cytosin H H CH₃ S4-(N,N-diacetyl)cytosine H H CH₃ S Uracil H H CH₃ S 5-Fluorouracilmonophosphate H CH₃ O 2,4-O-Diacetyluracil monophosphate H CH₃ OHypoxanthine monophosphate H CH₃ O 2,4-O-Diacetylthym monophosphate HCH₃ O Thymine monophosphate H CH₃ O Cytosine monophosphate H CH₃ O4-(N-mono-acetyl)cytosine monophosphate H CH₃ O 4-(N,N-diacetyl)cytosmonophosphate H CH₃ O Uracil monophosphate H CH₃ O 5-Fluorouracilmonophosphate H CH₃ S 2,4-O-Diacetyluracil monophosphate H CH₃ SHypoxanthine monophosphate H CH₃ S 2,4-O-Diacetylthym monophosphate HCH₃ S Thymine monophosphate H CH₃ S Cytosine monophosphate H CH₃ S4-(N-mono-acetyl)cytosine monophosphate H CH₃ S 4-(N,N-diacetyl)cytosinemonophosphate H CH₃ S Uracil monophosphate H CH₃ S 5-Fluorouracildiphosphate H CH₃ O 2,4-O-Diacetyluracil diphosphate H CH₃ OHypoxanthine diphosphate H CH₃ O 2,4-O-Diacetylthymine diphosphate H CH₃O Thymine diphosphate H CH₃ O Cytosine diphosphate H CH₃ O4-(N-mono-acetyl)cytosine diphosphate H CH₃ O 4-(N,N-diacetyl)cytosinediphosphate H CH₃ O Uracil diphosphate H CH₃ O 5-Fluorouracildiphosphate H CH₃ S 2,4-O-Diacetyluracil diphosphate H CH₃ SHypoxanthine diphosphate H CH₃ S 2,4-O-Diacetylthymine diphosphate H CH₃S Thymine diphosphate H CH₃ S Cytosine triphosphate H CH₃ O2,4-O-Diacetyluracil triphosphate H CH₃ O Hypoxanthine triphosphate HCH₃ O 2,4-O-Diacetylthymine triphosphate H CH₃ O Thymine triphosphate HCH₃ O Cytosine triphosphate H CH₃ O 4-(N-mono-acetyl)cytosinetriphosphate H CH₃ O 4-(N,N-diacetyl)cytosine triphosphate H CH₃ OUracil triphosphate H CH₃ O 5-Fluorouracil triphosphate H CH₃ S2,4-O-Diacetyluracil triphosphate H CH₃ S Hypoxanthine triphosphate HCH₃ S 2,4-O-Diacetylthymine triphosphate H CH₃ S Thymine triphosphate HCH₃ S Cytosine monophosphate monophosphate CF₃ O 2,4-O-Diacetyluracilmonophosphate monophosphate CF₃ O Hypoxanthine monophosphatemonophosphate CF₃ O 2,4-O-Diacetylthymine monophosphate monophosphateCF₃ O Thymine monophosphate monophosphate CF₃ O Cytosine monophosphatemonophosphate CF₃ O 4-(N-mono-acetyl)cytosine monophosphatemonophosphate CF₃ O 4-(N,N-diacetyl)cytosine monophosphate monophosphateCF₃ O Uracil monophosphate monophosphate CF₃ O 5-Fluorouracilmonophosphate monophosphate CF₃ S 2,4-O-Diacetyluracil monophosphatemonophosphate CF₃ S Hypoxanthine monophosphate monophosphate CF₃ S2,4-O-Diacetylthymine monophosphate monophosphate CF₃ S Thyminemonophosphate monophosphate CF₃ S Cytosine monophosphate monophosphateCF₃ S 4-(N-mono-acetyl)cytosine monophosphate monophosphate CF₃ S4-(N,N-diacetyl)cytosine monophosphate monophosphate CF₃ S Uracilmonophosphate monophosphate CF₃ S 5-Fluorouracil acetyl acetyl CF₃ O4-(N,N-diacetyl)cytosine acetyl acetyl CF₃ S 4-(N,N-diacetyl)cytosineacetyl acetyl 2- O 4-(N,N-diacetyl)cytosine bromo- vinyl acetyl acetyl2- S 4-(N,N-diacetyl)cytosine bromo- vinyl

Alternatively, the following nucleosides of Formula XV are prepared,using the appropriate sugar and pyrimidine or purine bases.

(XV)

R¹ R⁶ X Base H CH₃ O 2,4-O-Diacetyluracil H CH₃ O Hypoxanthine H CH₃ O2,4-O-Diacetylthymine H CH₃ O Thymine H CH₃ O Cytosine H CH₃ O4-(N-mono-acetyl)cytosine H CH₃ O 4-(N,N-diacetyl)cytosine H CH₃ OUracil H CH₃ O 5-Fluorouracil H CH₃ S 2,4-O-Diacetyluracil H CH₃ SHypoxanthine H CH₃ S 2,4-O-Diacetylthymine H CH₃ S Thymine H CH₃ SCytosine H CH₃ S 4-(N-mono-acetyl)cytosine H CH₃ S4-(N,N-diacetyl)cytosine H CH₃ S Uracil H CH₃ S 5-Fluorouracilmonophosphate CH₃ O 2,4-O-Diacetyluracil monophosphate CH₃ OHypoxanthine monophosphate CH₃ O 2,4-O-Diacetylthymine monophosphate CH₃O Thymine monophosphate CH₃ O Cytosine monophosphate CH₃ O4-(N-mono-acetyl)cytosine monophosphate CH₃ O 4-(N,N-diacetyl)cytosinemonophosphate CH₃ O Uracil monophosphate CH₃ O 5-Fluorouracilmonophosphate CH₃ S 2,4-O-Diacetyluracil monophosphate CH₃ SHypoxanthine monophosphate CH₃ S 2,4-O-Diacetylthymine monophosphate CH₃S Thymine monophosphate CH₃ S Cytosine monophosphate CH₃ S4-(N-mono-acetyl)cytosine monophosphate CH₃ S 4-(N,N-diacetyl)cytosinemonophosphate CH₃ S Uracil monophosphate CH₃ S 5-Fluorouracildiphosphate CH₃ O 2,4-O-Diacetyluracil diphosphate CH₃ O Hypoxanthinediphosphate CH₃ O 2,4-O-Diacetylthymine diphosphate CH₃ O Thyminediphosphate CH₃ O Cytosine diphosphate CH₃ O 4-(N-mono-acetyl)cytosinediphosphate CH₃ O 4-(N,N-diacetyl)cytosine diphosphate CH₃ O Uracildiphosphate CH₃ O 5-Fluorouracil diphosphate CH₃ S 2,4-O-Diacetyluracildiphosphate CH₃ S Hypoxanthine diphosphate CH₃ S 2,4-O-Diacetylthyminediphosphate CH₃ S Thymine diphosphate CH₃ S Cytosine triphosphate CH₃ O2,4-O-Diacetyluracil triphosphate CH₃ O Hypoxanthine triphosphate CH₃ O2,4-O-Diacetylthymine triphosphate CH₃ O Thymine triphosphate CH₃ OCytosine triphosphate CH₃ O 4-(N-mono-acetyl)cytosine triphosphate CH₃ O4-(N,N-diacetyl)cytosine triphosphate CH₃ O Uracil triphosphate CH₃ O5-Fluorouracil triphosphate CH₃ S 2,4-O-Diacetyluracil triphosphate CH₃S Hypoxanthine triphosphate CH₃ S 2,4-O-Diacetylthymine triphosphate CH₃S Thymine triphosphate CH₃ S Cytosine monophosphate CF₃ O2,4-O-Diacetyluracil monophosphate CF₃ O Hypoxanthine monophosphate CF₃O 2,4-O-Diacetylthymine monophosphate CF₃ O Thymine monophosphate CF₃ OCytosine monophosphate CF₃ O 4-(N-mono-acetyl)cytosine monophosphate CF₃O 4-(N,N-diacetyl)cytosine monophosphate CF₃ O Uracil monophosphate CF₃O 5-Fluorouracil monophosphate CF₃ S 2,4-O-Diacetyluracil monophosphateCF₃ S Hypoxanthine monophosphate CF₃ S 2,4-O-Diacetylthyminemonophosphate CF₃ S Thymine monophosphate CF₃ S Cytosine monophosphateCF₃ S 4-(N-mono-acetyl)cytosine monophosphate CF₃ S4-(N,N-diacetyl)cytosine monophosphate CF₃ S Uracil monophosphate CF₃ S5-Fluorouracil acetyl CF₃ O 4-(N,N-diacetyl)cytosine acetyl CF₃ S4-(N,N-diacetyl)cytosine acetyl 2-bromo-vinyl O 4-(N,N-diacetyl)cytosineacetyl 2-bromo-vinyl S 4-(N,N-diacetyl)cytosine

Alternatively, the following nucleosides of Formula XVIII are prepared,using the appropriate sugar and pyrimidine or purine bases.

(XVIII)

R¹ R⁶ R⁷ X Base R⁸ R⁹ H CH₃ OH O 2,4-O-Diacetyluracil H Me H CH₃ OH OHypoxanthine H Me H CH₃ OH O 2,4-O-Diacetylthymine H Me H CH₃ OH OThymine H Me H CH₃ OH O Cytosine H Me H CH₃ OH O4-(N-mono-acetyl)cytosine H Me H CH₃ OH O 4-(N,N-diacetyl)cytosine H MeH CH₃ OH O Uracil H Me H CH₃ OH O 5-Fluorouracil H Me H CH₃ OH S2,4-O-Diacetyluracil H Me H CH₃ OH S Hypoxanthine H Me H CH₃ OH S2,4-O-Diacetylthymine H Me H CH₃ OH S Thymine H Me H CH₃ OH S Cytosine HMe H CH₃ OH S 4-(N-mono-acetyl)cytosine H Me H CH₃ OH S4-(N,N-diacetyl)cytosine H Me H CH₃ OH S Uracil H Me H CH₃ OH S5-Fluorouracil H Me monophosphate CH₃ OH O 2,4-O-Diacetyluracil H Memonophosphate CH₃ OH O Hypoxanthine H Me monophosphate CH₃ OH O2,4-O-Diacetylthymine H Me monophosphate CH₃ OH O Thymine H Memonophosphate CH₃ OH O Cytosine H Me monophosphate CH₃ OH O4-(N-mono-acetyl)cytosine H Me monophosphate CH₃ OH O4-(N,N-diacetyl)cytosine H Me monophosphate CH₃ OH O Uracil H Memonophosphate CH₃ OH O 5-Fluorouracil H Me monophosphate CH₃ OH S2,4-O-Diacetyluracil H Me monophosphate CH₃ OH S Hypoxanthine H Memonophosphate CH₃ OH S 2,4-O-Diacetylthymine H Me monophosphate CH₃ OH SThymine H Me monophosphate CH₃ OH S Cytosine H Me monophosphate CH₃ OH S4-(N-mono-acetyl)cytosine H Me monophosphate CH₃ OH S4-(N,N-diacetyl)cytosine H Me monophosphate CH₃ OH S Uracil H Memonophosphate CH₃ OH S 5-Fluorouracil H Me diphosphate CH₃ OH O2,4-O-Diacetyluracil H Me diphosphate CH₃ OH O Hypoxanthine H Mediphosphate CH₃ OH O 2,4-O-Diacetylthymine H Me diphosphate CH₃ OH OThymine H Me diphosphate CH₃ OH O Cytosine H Me diphosphate CH₃ OH O4-(N-mono-acetyl)cytosine H Me diphosphate CH₃ OH O4-(N,N-diacetyl)cytosine H Me diphosphate CH₃ OH O Uracil H Mediphosphate CH₃ OH O 5-Fluorouracil H Me diphosphate CH₃ OH S2,4-O-Diacetyluracil H Me diphosphate CH₃ OH S Hypoxanthine H Mediphosphate CH₃ OH S 2,4-O-Diacetylthymine H Me diphosphate CH₃ OH SThymine H Me diphosphate CH₃ OH S Cytosine H Me triphosphate CH₃ OH O2,4-O-Diacetyluracil H Me triphosphate CH₃ OH O Hypoxanthine H Metriphosphate CH₃ OH O 2,4-O-Diacetylthymine H Me triphosphate CH₃ OH OThymine H Me triphosphate CH₃ OH O Cytosine H Me triphosphate CH₃ OH O4-(N-mono-acetyl)cytosine H Me triphosphate CH₃ OH O4-(N,N-diacetyl)cytosine H Me triphosphate CH₃ OH O Uracil H Metriphosphate CH₃ OH O 5-Fluorouracil H Me triphosphate CH₃ OH S2,4-O-Diacetyluracil H Me triphosphate CH₃ OH S Hypoxanthine H Metriphosphate CH₃ OH S 2,4-O-Diacetylthymine H Me triphosphate CH₃ OH SThymine H Me triphosphate CH₃ OH S Cytosine H Me monophosphate CF₃ OH O2,4-O-Diacetyluracil H Me monophosphate CF₃ OH O Hypoxanthine H Memonophosphate CF₃ OH O 2,4-O-Diacetylthymine H Me monophosphate CF₃ OH OThymine H Me monophosphate CF₃ OH O Cytosine H Me monophosphate CF₃ OH O4-(N-mono-acetyl)cytosine H Me monophosphate CF₃ OH O4-(N,N-diacetyl)cytosine H Me monophosphate CF₃ OH O Uracil H Memonophosphate CF₃ OH O 5-Fluorouracil H Me monophosphate CF₃ OH S2,4-O-Diacetyluracil H Me monophosphate CF₃ OH S Hypoxanthine H Memonophosphate CF₃ OH S 2,4-O-Diacetylthymine H Me monophosphate CF₃ OH SThymine H Me monophosphate CF₃ OH S Cytosine H Me monophosphate CF₃ OH S4-(N-mono-acetyl)cytosine H Me monophosphate CF₃ OH S4-(N,N-diacetyl)cytosine H Me monophosphate CF₃ OH S Uracil H Memonophosphate CF₃ OH S 5-Fluorouracil H Me acetyl CH₃ OH O4-(N,N-diacetyl)cytosine H Br acetyl CH₃ OH S 4-(N,N-diacetyl)cytosine HBr

VII. ANTI-FLAVIVIRUS OR PESTIVIRUS ACTIVITY

Compounds can exhibit anti-flavivirus or pestivirus activity byinhibiting flavivirus or pestivirus polymerase, by inhibiting otherenzymes needed in the replication cycle, or by other pathways.

EXAMPLES

The test compounds were dissolved in DMSO at an initial concentration of200 μM and then were serially diluted in culture medium.

Unless otherwise stated, baby hamster kidney (BHK-21) (ATCC CCL-10) andBos Taurus (BT) (ATCC CRL 1390) cells were grown at 37° C. in ahumidified CO₂ (5%) atmosphere. BHK-21 cells were passaged in Eagle MEMadditioned of 2 mM L-glutamine, 10% fetal bovine serum (FBS, Gibco) andEarle's BSS adjusted to contain 1.5 g/L sodium bicarbonate and 0.1 mMnon-essential amino acids. BT cells were passaged in Dulbecco's modifiedEagle's medium with 4 mM L-glutamine and 10% horse serum (HS, Gibco),adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose and 1.0mM sodium pyruvate. The vaccine strain 17D (YFV-17D) (Stamaril®, PasteurMerieux) and Bovine Viral Diarrhea virus (BVDV) (ATCC VR-534) were usedto infect BHK and BT cells, respectively, in 75 cm² bottles. After a 3day incubation period at 37° C., extensive cytopathic effect wasobserved. Cultures were freeze-thawed three times, cell debris wereremoved by centrifugation and the supernatant was aliquoted and storedat −70° C. YFV-17D and BVDV were titrated in BHK-21 and BT cells,respectively, that were grown to confluency in 24-well plates.

Example 4 Phosphorylation Assay of Nucleoside to Active Triphosphate

To determine the cellular metabolism of the compounds, HepG2 cells wereobtained from the American Type Culture Collection (Rockville, Md.), andwere grown in 225 cm² tissue culture flasks in minimal essential mediumsupplemented with non-essential amino acids, 1% penicillin-streptomycin.The medium was renewed every three days, and the cells were subculturedonce a week. After detachment of the adherent monolayer with a 10 minuteexposure to 30 mL of trypsin-EDTA and three consecutive washes withmedium, confluent HepG2 cells were seeded at a density of 2.5×10⁶ cellsper well in a 6-well plate and exposed to 10 μM of [³H] labeled activecompound (500 dpm/pmol) for the specified time periods. The cells weremaintained at 37° C. under a 5% CO₂ atmosphere. At the selected timepoints, the cells were washed three times with ice-coldphosphate-buffered saline (PBS). Intracellular active compound and itsrespective metabolites were extracted by incubating the cell pelletovernight at −20° C. with 60% methanol followed by extraction with anadditional 20 μL of cold methanol for one hour in an ice bath. Theextracts were then combined, dried under gentle filtered air flow andstored at −20° C. until HPLC analysis. The preliminary results of theHPLC analysis are tabulated in Table 1.

TABLE 1 [pmol/million cells] β-D-2′-CH₃- β-D-2′-CH₃- β-D-2′-CH₃-β-D-2′-CH₃- Time (h) riboA-TP riboU-TP riboC-TP riboG-TP 2 33.1 0.402.24 ND 4 67.7 1.21 3.99 ND 8 147 1.57 9.76 2.85 24 427 6.39 34.9 0.9130 456 7.18 36.2 3.22 48 288 9.42 56.4 6.26

Example 5 Bioavailability Assay in Cynomolgus Monkeys

Within 1 week prior to the study initiation, the cynomolgus monkey wassurgically implanted with a chronic venous catheter and subcutaneousvenous access port (VAP) to facilitate blood collection and underwent aphysical examination including hematology and serum chemistryevaluations and the body weight was recorded. Each monkey (six total),received approximately 250 uCi of ³H activity with each dose of activecompound, namely β-D-2′-CH₃-riboG at a dose level of 10 mg/kg at a doseconcentration of 5 mg/mL, either via an intravenous bolus (3 monkeys,IV), or via oral gavage (3 monkeys, PO). Each dosing syringe was weighedbefore dosing to gravimetrically determine the quantity of formulationadministered. Urine samples were collected via pan catch at thedesignated intervals (approximately 18-0 hours pre-dose, 0-4, 4-8 and8-12 hours post-dosage) and processed. Blood samples were collected aswell (pre-dose, 0.25, 0.5, 1, 2, 3, 6, 8, 12 and 24 hours post-dosage)via the chronic venous catheter and VAP or from a peripheral vessel ifthe chronic venous catheter procedure should not be possible. The bloodand urine samples were analyzed for the maximum concentration (C_(max)),time when the maximum concentration was achieved (T_(max)), area underthe curve (AUC), half life of the dosage concentration (T_(1/2)),clearance (CL), steady state volume and distribution (V_(ss)) andbioavailability (F), which are tabulated in Tables 2 and 3, andgraphically illustrated in FIGS. 2 and 3, respectively.

TABLE 2 Oral Bioavailability in Monkeys AUC Norm AUC Dose (ng/ (ng/ MeanNorm AUC (mg) mL × h) mL × h/mg) (ng/mL × h/mg) F (%) IV Monkey 1 46.4413614 293.2 IV Monkey 2 24.53 6581 268.3 IV Monkey 3 20.72 6079 293.4284.9 PO Monkey 1 29.04 758 26.1 PO Monkey 2 30.93 898 29.0 PO Monkey 330.04 1842 61.3 38.8 13.6

TABLE 3 Experimental Pharmacokinetics of β-D-2′-CH₃-riboG in CynomolgusMonkeys IV PO Dose/Route (mg/kg) 10 10 C_(max) (ng/mL) 6945.6 ± 1886.0217.7 ± 132.1 T_(max) (hr) 0.25 ± 0.00 2.00 ± 1.00 AUC (ng/mL × hr)8758.0 ± 4212.9 1166.0 ± 589.6  T_(1/2) (hr) 7.9 ± 5.4 10.3 ± 4.1  CL(L/hr/kg) 1.28 ± 0.48 V_(ss) (L/kg) 2.09 ± 0.54 F (%) 13.8

Example 6 Bone Marrow Toxicity Assay

Human bone marrow cells were collected from normal healthy volunteersand the mononuclear population was separated by Ficoll-Hypaque gradientcentrifugation as described previously by Sommadossi J-P, Carlisle R.“Toxicity of 3′-azido-3′-deoxythymidine and9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoieticprogenitor cells in vitro” Antimicrobial Agents and Chemotherapy 1987;31:452-454; and Sommadossi J-P, Schinazi R F, Chu C K, Xie M-Y.“Comparison of cytotoxicity of the (−)- and (+)-enantiomer of2′,3′-dideoxy-3′-thiacytidine in normal human bone marrow progenitorcells” Biochemical Pharmacology 1992; 44:1921-1925. The culture assaysfor CFU-GM and BFU-E were performed using a bilayer soft agar ormethylcellulose method. Drugs were diluted in tissue culture medium andfiltered. After 14 to 18 days at 37° C. in a humidified atmosphere of 5%CO₂ in air, colonies of greater than 50 cells were counted using aninverted microscope. The results in Table 4 are presented as the percentinhibition of colony formation in the presence of drug compared tosolvent control cultures.

TABLE 4 Human Bone Marrow Toxicity CFU-GM and BFU-E Clonogenic AssaysIC₅₀ in μM Treatment CFU-GM BFU-E ribavirin ~5 ~1β-D-2′-CH₃-riboA >100 >100 β-D-2′-CH₃-riboU >100 >100β-D-2′-CH₃-riboC >10 >10 β-D-2′-CH₃-riboG >10 >100

Example 7 Mitochondria Toxicity Assay

HepG2 cells were cultured in 12-well plates as described above andexposed to various concentrations of drugs as taught by Pan-Zhou X-R,Cui L, Thou X-J, Somrnadossi J-P, Darley-Usmer V M. “Differentialeffects of antiretroviral nucleoside analogs on mitochondrial functionin HepG2 cells” Antimicrob Agents Chemother 2000; 44:496-503. Lacticacid levels in the culture medium after 4 day drug exposure was measuredusing a Boehringer lactic acid assay kit. Lactic acid levels werenormalized by cell number as measured by hemocytometer count. Thepreliminary results from this assay are tabulated in Table 5.

TABLE 5 Mitochondrial Toxicity Study (L-lactic acid assay) Conc. (μM)lactate (mg/10⁶ cell) % of Control Control 2.18 FIAU 10 3.73 170.4β-D-2′-CH₃-riboC 1 2.52 115.3 10 2.36 107.9 50 2.26 103.4 100 2.21 101.2

Example 8 Cytotoxicity Assay

Cells were seeded at a rate of between 5×10³ and 5×10⁴/well into 96-wellplates in growth medium overnight at 37° C. in a humidified CO₂ (5%)atmosphere. New growth medium containing serial dilutions of the drugswas then added. After incubation for 4 days, cultures were fixed in 50%TCA and stained with sulforhodamineB. The optical density was read at550 nm. The cytotoxic concentration was expressed as the concentrationrequired to reduce the cell number by 50% (CC₅₀). The data is tabulatedin Table 6.

TABLE 6 MDBK versus Human Hepatoma CC₅₀, μM Compound MDBK Huh7 HepG2β-D-2′-CH₃-riboA 20 40 50-60 β-D-2′-CH₃-riboU >250 >250 >250β-D-2′-CH₃-riboC 100 >250 150 β-D-2′-CH₃-riboG 100 >250 >250 Ribavirin 525 150

Example 9 Cell Protection Assay (CPA)

The assay was performed essentially as described by Baginski, S. G.;Pevear, D. C.; Seipel, M.; Sun, S. C. C.; Benetatos, C. A.; Chunduru, S.K.; Rice, C. M. and M. S. Collett “Mechanism of action of a pestivirusantiviral compound” PNAS USA 2000, 97(14), 7981-7986. MDBK cells (ATCC)were seeded onto 96-well culture plates (4,000 cells per well) 24 hoursbefore use. After infection with BVDV (strain NADL, ATCC) at amultiplicity of infection (MOI) of 0.02 plaque forming units (PFU) percell, serial dilutions of test compounds were added to both infected anduninfected cells in a final concentration of 0.5% DMSO in growth medium.Each dilution was tested in quadruplicate. Cell densities and virusinocula were adjusted to ensure continuous cell growth throughout theexperiment and to achieve more than 90% virus-induced cell destructionin the untreated controls after four days post-infection. After fourdays, plates were fixed with 50% TCA and stained with sulforhodamine B.The optical density of the wells was read in a microplate reader at 550nm. The 50% effective concentration (EC₅₀) values were defined as thecompound concentration that achieved 50% reduction of cytopathic effectof the virus. The results are tabulated in Table 7. FIGS. 4 and 5provide a graphical illustration of the methodology used to arrive atthe 50% effective concentration (EC₅₀) values for β-D-2′-CH₃-riboG andribavirin. FIG. 6 compares the results of the CPA for β-D-2′-CH₃-riboG,β-D-2′-CH₃-riboC, β-D-2′-CH₃-riboU, β-D-2′-CH₃-riboA and ribavirin

TABLE 7 Cell Protection Assay EC₅₀, μM CC₅₀, μM β-D-2′-CH₃-riboA 2 20β-D-2′-CH₃-riboU 20 >250 β-D-2′-CH₃-riboC 2 100 β-D-2′-CH₃-riboG 4 100Ribavirin >3 5

Example 10 Plaque Reduction Assay

For each compound the effective concentration was determined induplicate 24-well plates by plaque reduction assays. Cell monolayerswere infected with 100 PFU/well of virus. Then, serial dilutions of testcompounds in MEM supplemented with 2% inactivated serum and 0.75% ofmethyl cellulose were added to the monolayers. Cultures were furtherincubated at 37° C. for 3 days, then fixed with 50% ethanol and 0.8%Crystal Violet, washed and air-dried. Then plaques were counted todetermine the concentration to obtain 90% virus suppression andtabulated in Table 8. FIG. 7 is a graphical illustration of the resultsfrom the Plaque Reduction Assay. FIG. 8 is an image of BVDV plaqueformation in the presence of increasing concentrations ofβ-D-2′-CH₃-riboU.

TABLE 8 Viral Suppression via Plaque Reduction Assay EC₉₀, μMβ-D-2′-CH₃-riboA <3 β-D-2′-CH₃-riboU <81 β-D-2′-CH₃-riboC <9β-D-2′-CH₃-riboG <9

Example 11 Yield Reduction Assay

For each compound the concentration to obtain a 6-log reduction in viralload was determined in duplicate 24-well plates by yield reductionassays. The assay was performed as described by Baginski, S. G.; Pevear,D. C.; Seipel, M.; Sun, S. C. C.; Benetatos, C. A.; Chunduru, S. K.;Rice, C. M. and M. S. Collett “Mechanism of action of a pestivirusantiviral compound” PNAS USA 2000, 97(14), 7981-7986, with minormodifications. Briefly, MDBK cells were seeded onto 24-well plates(2×105 cells per well) 24 hours before infection with BVDV (NADL strain)at a multiplicity of infection (MOI) of 0.1 PFU per cell. Serialdilutions of test compounds were added to cells in a final concentrationof 0.5% DMSO in growth medium. Each dilution was tested in triplicate.After three days, cell cultures (cell monolayers and supernatants) werelysed by three freeze-thaw cycles, and virus yield was quantified byplaque assay. Briefly, MDBK cells were seeded onto 6-well plates (5×105cells per well) 24 h before use. Cells were inoculated with 0.2 mL oftest lysates for 1 hour, washed and overlaid with 0.5% agarose in growthmedium. After 3 days, cell monolayers were fixed with 3.5% formaldehydeand stained with 1% crystal violet (w/v in 50% ethanol) to visualizeplaques. The plaques were counted to determine the concentration toobtain a 6-log reduction in viral load as tabulated in Table 9. FIG. 9is a graphical illustration of the results from the Yield ReductionAssay. FIG. 8 is an image of BVDV yield reduction in the presence ofincreasing concentrations of β-D-2′-CH₃-riboC.

TABLE 9 Concentration to Obtain 6-log Reduction Conc. for 6-logReduction (μM) β-D-2′-CH₃-riboU 120 β-D-2′-CH₃-riboG 20 β-D-2′-CH₃-riboC20 β-D-2′-CH₃-riboA 9

Example 12 Comparative Cytotoxicity

Table 10 summarizes the cytoxicity of two compounds of this invention,β-D-1′-CH₃-riboA and β-D-2′-CH₃-riboA, in comparison to RBV(“ribavirin”), in various cell systems.

TABLE 10 Comparative Cytotoxicity* (CC₅₀) BD BHK VERO MT-4β-D-1′-CH₃-riboA >100 200 >100 18 β-D-2′-CH₃-riboA 75 22 22 6.6 RBV ND50 11 ND *Compound concentration (μM) required to reduce the viabilityof cells by 50%.

The chemical structures for β-D-1′-CH₃-riboA and β-D-2′-CH₃-riboA are asfollows:

Table 11 summarizes the antiviral activity of β-D-1′-CH₃-riboA andβ-D-2′-CH₃-riboA against several viruses within the flavivirus andpestivirus genuses.

TABLE 11 Comparative Antiviral Activity* (EC₅₀) BVDV YFV PICO VSV HIV-1β-D-1′-CH3-riboA 10 7.0 51 >100 >18 β-D-2′-CH3-riboA 0.1 0.25.0 >100 >6.6 RBV ND 30 >30 ND ND *Compound concentration (μM) requiredto reduce the plaque number by 50%. The following virus-cell system wereused: BVDC-BT, YFV-BHK, PICO (Cosxackie B1 and Polio Sabin)/VSV − Vero.

Table 12 summarizes the antiviral activity and toxicity ofβ-D-2′-methyl-riboG, β-D-2′-methyl-riboC and β-D-2′-methyl-riboU,against a couple of viruses within the flavivirus and pestivirusgenuses.,

TABLE 12 Comparative Antiviral Activity* (EC₅₀) BVDV YFV EC₅₀* CC₅₀**EC₅₀* CC₅₀** β-D-2′-CH₃-riboG 2 >100 1.2 20 β-D-2′-CH₃-riboC 3.7 >10070 >100 β-D-2′-CH₃-riboU 20 >100 33 >100 *Compound concentration (μM)required to reduce the plaque number by 50%. The following virus-cellsystem were used: BVDC-BT and YFV-BHK. *Compound concentration (μM)required to reduce the viability of cells by 50%.

The chemical structures for β-D-2′-CH₃-riboG, β-D-2′-CH₃-riboC andβ-D-2′-CH₃-riboU are as follows:

Table 13 summarizes the anti-viral activity of several compounds of thisinvention against BVDV in three different assays.

TABLE 13 for BVDV Yield Reduction Plaque 6 log₁₀ Cytotoxicity CellProtection Reduction reduction Huh7 cells Compound (EC₅₀, μM) (EC₉₀, μM)EC₉₀, μM (μM) (EC₅₀, μM) β-D-2′-CH₃-riboA 2 <3 <2 9 50β-D-2′-CH₃-riboT >250 ND ND ND >250 β-D-2′-CH₃-riboU 20 <81 24 120 >250β-D-2′-CH₃-riboC 2 <9 <4 20 >250 β-D-2′-CH₃-riboG 4 <9 3 20 >250β-D-2′-CH₃-riboI 45 ND ND ND >250 Ribavirin >3 >200 >20 toxic 20

This invention has been described with reference to its preferredembodiments. Variations and modifications of the invention, will beobvious to those skilled in the art from the foregoing detaileddescription of the invention.

1-30. (canceled)
 31. A method for the treatment of a Flaviviridaeinfection in a host, comprising administering to said host ananti-virally effective amount of a β-D-2′-methyl-ribofuranosylnucleoside or a phosphate thereof, or a pharmaceutically acceptable saltor ester thereof.
 32. The method of claim 31, wherein an anti-virallyeffective amount of a β-D-2′-methyl-ribofuranosyl nucleoside or aphosphate thereof, or a pharmaceutically acceptable ester thereof isadministered.
 33. The method of claim 32, wherein the nucleoside is apyrimidine nucleoside.
 34. The method of claim 33, wherein theβ-D-2′-methyl-ribofuranosyl pyrimidine nucleoside is administered incombination or alternation with a second anti-Flaviviridae agent. 35.The method of claim 34, wherein the second anti-Flaviviridae agent is aninterferon.
 36. The method of claim 34, wherein the secondanti-Flaviviridae agent is ribavirin.
 37. The method of claim 34,wherein the second anti-Flaviviridae agent is an interferon, ribavirin,or a combination thereof.
 38. The method of claim 31, wherein thenucleoside is a pyrimidine nucleoside.
 39. The method of claim 38,wherein the β-D-2′-methyl-ribofuranosyl pyrimidine nucleoside isadministered in combination or alternation with a secondanti-Flaviviridae agent.
 40. The method of claim 39, wherein the secondanti-Flaviviridae agent is an interferon.
 41. The method of claim 39,wherein the second anti-Flaviviridae agent is ribavirin.
 42. The methodof claim 39, wherein the second anti-Flaviviridae agent is aninterferon, ribavirin, or a combination thereof.
 43. The method of claim31, wherein the β-D-2′-methyl-ribofuranosyl nucleoside or a phosphatethereof, or a pharmaceutically acceptable salt or ester thereof is in atablet or capsule.
 44. The method of claim 31, wherein a unit dose ofthe β-D-2′-methyl-ribofuranosyl nucleoside or a phosphate thereof, or apharmaceutically acceptable salt or ester thereof is administered. 45.The method of claim 43, wherein the tablet or capsule contains 50 to1000 mg of the β-D-2′-methyl-ribofuranosyl nucleoside or a phosphatethereof, or a pharmaceutically acceptable salt or ester thereof.
 46. Themethod of claim 44, wherein the unit dose contains 50 to 1000 mg of theβ-D-2′-methyl-ribofuranosyl nucleoside or a phosphate thereof, or apharmaceutically acceptable salt or ester thereof.
 47. The method ofclaim 31, wherein the nucleoside is aβ-D-2′-methyl-2′-halo-ribofuranosyl nucleoside or a phosphate thereof,or a pharmaceutically acceptable salt or ester thereof.
 48. The methodof claim 47, wherein an anti-virally effective amount of aβ-D-2′-methyl-2′-halo-ribofuranosyl nucleoside, or a phosphate thereof,or a pharmaceutically acceptable ester thereof is administered.
 49. Themethod of claim 48, wherein the nucleoside is aβ-D-2′-methyl-2′-halo-ribofuranosyl pyrimidine nucleoside.
 50. A methodfor the treatment of a Flaviviridae infection in a host, comprisingadministering to the host an anti-virally effective amount of a compoundof Formula XI:

or a pharmaceutically acceptable salt or ester thereof; wherein: Base isa pyrimidine base; R¹ and R² are each independently H or phosphate; R⁶is alkyl; R⁷ is halo; and X is O.
 51. The method of claim 50, whereinBase is uracil.
 52. The method of claim 51, wherein R⁶ is methyl. 53.The method of claim 52, wherein R¹ is phosphate.
 54. The method of claim53, wherein R² is H.
 55. The method of claim 50, wherein the compound ofFormula XI is administered in combination or alternation with a secondanti-Flaviviridae agent.
 56. The method of claim 55, wherein the secondanti-Flaviviridae agent is an interferon.
 57. The method of claim 55,wherein the second anti-Flaviviridae agent is ribavirin.
 58. The methodof claim 55, wherein the second anti-Flaviviridae agent is aninterferon, ribavirin, or a combination thereof
 59. The method of claim54, wherein the compound of Formula XI is administered in combination oralternation with a second anti-Flaviviridae agent.
 60. The method ofclaim 59, wherein the second anti-Flaviviridae agent is an interferon,ribavirin or a combination thereof.